A successful University of Chicago-trained, Chicago based vascular surgeon, Richard returns home from an operation after a fundraiser one evening to find His wife Helen dead following a violent attack and a mysterious one-armed man with a prosthetic right arm. Richard fights the man and then calls the police after the killer manages to escape. Despite His testimony about The One-Armed Man, Richard is convicted of first degree murder, due to the lack of evidence of a break-in, His being the sole beneficiary of Helen's lucrative life insurance policy, a misunderstood 9-1-1 call, His fingerprints found on the lamp and the gun that they own and some minor scratches caused by His wife's finger nails with some of His skin under her nails. At His trial, Richard is found guilty and is sentenced to death via lethal injection.
During the bus ride to death row, one of the other three prisoners fakes a seizure and begins to foam at the mouth as if he was poisoned. A guard unlocks the cage separating him from the prisoners to assist him. The prisoner then stabs the guard with a shank made from a concealed sharpened toothbrush and chaos ensues. Another guard shoots the prisoner with a shotgun, then a second prisoner tries to grab the gun from the guard, but in the struggle, the gun goes off and kills the driver. The bus crashes through a guardrail, rolls down a hill and lands on a railroad track. The light from an approaching freight train appears and Richard manages to pull himself and one of the guards to safety just as the train rams into the bus at speed. The bus is dragged on the front of the first locomotive for several hundred feet, but upon crossing a short bridge, the first locomotive's coupler breaks and every car from the second engine on back derails. Richard manages to outrun the derailing locomotive as it buries itself nose-first into the ground. Richard is then freed from His chains by Copeland, the only other surviving prisoner and they both escape from the scene on foot.
A car arrives at the crash site, containing Deputy United States Marshal Samuel Gerard, who leads a team from the US Marshals Service Fugitive Task Force. They observe the debris and Gerard finds the local sheriff, Rollins, interviewing the old guard who survived the wreck with some minor injuries. The guard, given the suddenness of the wreck, is under the impression that all of the prisoners were killed and takes false credit for saving the other one (when in actuality, He left the other guard to die with Richard & Copeland). Gerard requests for Rollins to establish Police checkpoints, which Rollins is skeptical of doing until Gerard requests to have jurisdiction passed over to him. Just then, Deputy Bobby Biggs recovers a pair of unshackled leg irons and a manhunt for Richard begins.
The next morning, as the Marshals watch the cleanup work, the younger guard, the one who was wounded in the revolt, is extricated alive underneath debris from one of the locomotives after being trapped for more than twelve hours.
There are many close calls where Richard almost gets arrested, mostly brought on by His compassionate instincts. The first instance is at a hospital after Richard heals His wounds, shaves off His beard and changes into a doctor's uniform. He easily avoids being detected by a state trooper at the hospital on the lookout for him, as the trooper only noticed that Richard's Pants were unzipped. Richard also happens to be present when the ambulance containing the wounded guard arrives and He helps the paramedics unfold the wheels on the gurney. The two men recognize each other, but Richard quietly puts the guard's breathing mask down to keep him quiet and gives the paramedics a detailed description of the guard's injuries, which astonishes them. As soon as they're inside, Richard steals their ambulance.
Richard is first discovered when he uses the lights and siren going through a grade crossing. He is pursued by the Illinois State Police on land and by Gerard in a helicopter running alongside the highway. Richard is then forced to a halt by a Police road block in a tunnel near a dam. He exits the ambulance and is pursued by Gerard through the dam's drainage system. At one point, Gerard falls and drops His gun in the water, only to find Richard holding it and aiming it at him. Richard insists on His innocence, but Gerard, whose mission is simply to arrest Richard and not to solve the crime, tells him that He doesn't care. Richard tries to continue running, but Gerard takes out a back up gun and eventually traps him near the end of a spillway. Richard escapes by doing a backflip off of the dam and into the water below.
The encounter with Gerard at the dam makes Richard realize that the authorities will always accept His guilt as a matter of fact and that the only way for him to recover His freedom is by finding His wife's killer. The fact that Richard pointed Gerard's gun at him during this encounter gives Gerard a strong motive to pursue his fugitive vigorously. After spending the night in the middle of the woods and having a nightmare about Helen's murder, Richard eventually makes his way to a truck stop and dyes his hair to conceal himself more easily. As he walks down the road, a woman picks him up and offers him a ride, which he accepts.
The Next day, Richard returns to Chicago to continue His search for The One-Armed Man who killed Helen, believing that the he might still be there. He calls his lawyer, Walter Guthrie and asks for help and money, but Guthrie says he'd be harboring and aiding a convicted felon and can't help him like that. Guthrie says as Richard's friend Legal counselor that Richard should just give himself up. When Guthrie asks Richard where he is, Richard says that he's in ST. Louis as he knows that his call is being traced. At the Marshals' Office, Gerard is told off over the phone by his boss for killing Copeland (who was found alive and was also wanted for questioning on Richard's whereabouts). But Gerard Justifies his actions because during the raid to arrest Copeland, he had taken Deputy Noah Newman hostage and was going to kill him with his own gun, leading Gerard to Shoot Copeland as he never bargains with hostage takers. When Gerard and the Marshals listen in on the wiretapped conversation between Richard and Guthrie, Marshal Henry makes out the sounds of an elevated train (which at the time of filming wasn't part of ST. Loius) rumbling by overhead. Further enhancement reveals a P.A. announcer on board an 'L' train saying, "Next Stop: Merchandise Mart" and the bell from the wells street bridge, which tells them that Richard's back in the city. Enlisting the Chicago Police Department for help as the Marshals continue their search for Richard, Gerard tells Deputy Cosmo Renfro that he wants to re-interview the hospital staff then explains to Detectives Kelly and Rossetti that he doesn't want to use the media in the hunt and that they should let Richard try to relax and re-enter his life somewhere.
Richard makes contact with many of his former medical friends and associates, virtually all of whom have never believed him to be guilty and are more than willing to help him. Richard also meets his close friend Dr. Charles Nichols, a pathologist who works also for Devlin-McGregor pharmaceuticals. Nichols gives Richard money, becomes a contact for Him and offers to help in any way. Later, when confronted by Gerard, Renfro & Biggs, Nichols boldly tells them to give up because Richard is too smart to ever be arrested.
Richard rents a basement apartment and makes fake ID cards to pose as a janitor to get access to Cook County Hospital, where he hopes to search the computers in the prosthetic limb department for patient information matching the description of The One-Armed Man.
Unfortunately, the land lady's son is a drug dealer, as Richard only finds this out when he wakes up the next morning, after having another nightmare about Helen's murder. As he wakes up, Richard hears a series of car doors slamming out front. He looks out and sees the Police running towards the house. A few of the officers break down the front door of the house while, tactical assault officers circle it looking to cut off all of the escape routes. Curiously, none of them head for the basement. Richard then hears footsteps above, as the dealer and his accomplice upstairs try to break for it. They burst out of a back door and run down the steps to the yard, where the Police arrest them, handcuff them and lead them away.
The drug dealer informs the Police that Richard is living with them, leading the Marshals to investigate his apartment. At Cook County Hospital, Richard finds and prints out names, addresses and phone numbers for five men who have the same type of prosthetic arm as his wife's killer and their previous adjustment dates. As Richard leaves the prosthetics department, he notices a whole bunch of Doctors and nurses treating a lot of kids who were in a bus crash and is asked by a female Doctor to move one of the boys to an observation room. Richard had noticed the boy having severe chest pains and being misdiagnosed, so he changes the boy's form so that he can have a life saving surgery. Richard is then confronted by the same doctor who asked him to move the boy, but he manages to escape. Gerard, always in hot pursuit, arrives with the Marshals and the Police and learns about Richard saving the boy's life, which leads him and Renfro to wonder why someone as smart as Richard would risk being arrested by going to such a high-profile place as a hospital. At that moment, they see a One-Armed Man walk by and they realize what Richard was probably up to.
Going through the list of men with prosthetic right arms, Richard is unsuccessful with the first two, the second one having died recently, but he discovers that the third man, Clive Driscoll, is in prison for armed robbery. He visits the man, but sees that Driscoll isn't the killer whom he faught with inside his house. Trying to understand Richard's movements, Gerard also finds Driscoll on a list of 47 One-Armed Men, who are all cross-checked for criminal records. Gerard arrives shortly after Richard, giving him a close call when they pass on the stairs, but he manages to escape into the Saint Patrick's Day parade, donning a hat to disguise himself.
The next day, Richard checks the fourth name on the list: Frederick Sykes. When he is unable to reach Sykes by phone, Richard breaks into Sykes' residence. In the apartment, Richard finds that Sykes, a former Police Officer, is the man who killed his wife as well as a prosthetic arm similar to the one he remembered on the killer. He also finds some photos in Sykes' desk drawer, some of which show Sykes with another Pathologist who he met at the party on the night of the murder, Dr. Alec Lentz, who also works for Devlin-McGregor, which sponsored the fundraiser, as well as a time card showing that Sykes works for them and information on Provasic, the company's new artery cleaning & cholesterol lowering Pill. Richard had previously investigated the new medication and discovered that it caused severe Drug-induced hepatitis, which would've prevented it from being approved by the FDA. Richard then remembers that the patient who he had to perform an emergency operation for on the night of his wife's murder was a man from Provasic's testing department, who also had a severely damaged liver. All of these revelations cause Richard to realize that Sykes' presence in his house wasn't an attempted robbery, but an orchestrated hit and that he was the original target.
Richard then places a call to the Marshals' office, which had previously been getting crank calls by men pretending to be him. After talking with Gerard, Richard leaves the phone off the hook knowing that they have a tap on it and leaves Sykes' apartment. Gerard and the Marshals successfully trace the call to Sykes' home and along with the Police, they conduct a search of the place. Eventually, Sykes returns home and Gerard questions him. Sykes sarcastically professes his guilt, but lies about his alibi stating that 15 other people can vouch for his presence out of town on a business trip that night, as he had told the Police when they first questioned him about Helen's murder. Gerard learns that Sykes is now working as a security guard for Devlin-McGregor, handling security for their top executives and that he lost his right arm in the line of duty when working for the CPD. While the Police believe Sykes, the Marshals however are skeptical and they set up surveillance outside of his residence. Gerard is also aware of the photo that Richard was looking at, due to fingerprinting of the apartment and assigns Newman to check out the identity of Lentz in the photo.
Richard calls Nichols, claiming that he now knows who was behind his wife's murder. Nichols explains to Richard that this might not hold up, as Lentz is dead: he died in a car accident the previous year. Richard still wants to double-check his findings and asks Nichols to call hospital associate Bones Roosevelt to look over the samples.
Shortly after this, Gerard and Renfro meet with Nichols, questioning him about Sykes and the photo. Nichols claims he doesn't recognize Sykes or Lentz. Returning to their headquarters, Newman explains that in digging deeper, he found that on a blowup of the picture of Lentz and Sykes, Lentz is wearing a shirt that mentions Chicago Memorial Hospital and goes there to investigate.
Newman and Biggs go to the hospital, learn of Lentz's identity and are referred to Roosevelt. When Newman mentions Dr. Kimble, Roosevelt grows uneasy before finally admitting that he had seen Richard previously when he came by to pick up some tissue samples. Upon further investigation, Roosevelt also answers some questions regarding Lentz. It actually turns out that the medicine's release was approved by Nichols, who was Lentz's boss. This revelation is relayed to Gerard, who now wants to bring Nichols in, on the basis that he lied regarding their investigation.
Meanwhile, Richard takes the tissue samples to former associate, Dr. Kathy Wahlund. Checking the samples, they see that they've been tampered with and that they all came from the same healthy liver. Richard believes that Lentz threw out the damaged tissue samples he was sending him and replaced it with the healthy one, but Wahlund notes that half of the samples that Lentz approved of were signed on the day that he died. Thinking someone else with access to Lentz may have been behind this, Richard immediately realizes that this whole time it was Dr. Nichols and goes to confront him.
At their Office, Gerard and the Marshals go over the report on Lentz's death. Marshal Stevens comes in saying that in going through Richard's phone records, he found that Richard called Sykes from his car phone on the night of the murder. Going through the report on Richard, they find that the call was made at 7:30 PM, which was when Richard was still at the party. Gerard requests that Sykes be brought in for immediate questioning. Deputy Erin Poole then tells the marshals that she was informed that Sykes isn't home as Sykes had escaped from the cops after Nichols called the fire department, allowing him to walk away in the chaos.
Richard takes an elevated train to a Hotel where Nichols is giving a speech that night as a keynote speaker at a medical conference. On the train, a Man notices Richard from his picture in the newspaper and goes to tell a Transit Officer. Just then Sykes, who had been trailing Richard from the hospital on Nichols' orders, appears and points his gun at Richard and forces him to move toward the doors. Their confrontation is interrupted by the officer who pulls his gun on Richard. Sykes shoots and kills the Cop, but Richard uses the distraction To pull the emergency brake as the train comes into Clark/Lake station and he manages to subdue Sykes. Richard then takes both guns, handcuffs Sykes to a pole on the train and then knocks him unconscious. Richard then breaks a window and escapes from the train on foot. Several witnesses notice Richard heading towards the Hotel and this is radioed to the CPD and to the Marshals. A Big concern to Gerard is that word of an 'officer down' has made Richard a dangerous suspect in the eyes of the Chicago Police, who will most likely take him down as soon as they can.
Richard takes the bullets out of the guns before he disposes of them and then manages to make his way to the conference room in the Hotel, where Nichols is giving a speech in regards to the approval and release of Provasic. Nichols attempts to usher Richard quietly into a small suite off to the side of the conference room, but Richard vocally accuses Nichols regarding his motive: Dr. Nichols falsified his research, orchestrated Helen's Murder and most likely killed Lentz before framing him.
Once in the suite, Nichols attacks Richard and the two scuffle in the room, before it eventually spills out onto the Hotel's rooftop.
The Marshals arrive, but are told to stay out of the situation by the CPD. Gerard and the other Marshals storm past the Police and he eventually finds where Richard went as the building is locked down. Gerard then makes his way to the rooftop and watches as Richard and Nichols fight, before the two of them plummet through a skylight and fall atop an elevator that then descends.
The chase eventually leads them to the Hotel's laundry room on the fifth floor. Nichols, who landed in front of the doors, recovers from the fall first, but Richard is soon behind him, as are Gerard and Renfo, who make it to the fifth floor and clear out the staff. Gerard calls out to Richard and tells him that he's not only trapped, but the CPD thinks that he killed the officer on the train and that he'll be shot on site if he doesn't give himself up. Gerard also says that he knows of Richard's innocence, as well as what really happened on the night of his wife's murder: Nichols had borrowed Richard's Car and he had the keys to his house, which was how Sykes got in without forced entry and Nichols also telephoned Sykes from Richard's car. Nichols manages to knock out Renfro with a hanging girder and then takes his gun to shoot Gerard, but Richard takes a steel pipe and knocks him out.
In the aftermath, Sykes and Nichols are taken into custody and Gerard escorts Richard out of the Hotel in handcuffs. In the back of their car, Gerard removes the handcuffs and gives Richard a small bag of ice for his bruised hands. The car then pulls away as Richard is exonerated.