Dr. Richard Kimble, a prominent Chicago vascular surgeon, arrives home to find his wife Helen fatally wounded by a one-armed man. Kimble struggles with the killer but he escapes. The lack of evidence of a break-in, Helen’s lucrative life insurance policy, and a misunderstood 9-1-1 call result in Kimble’s wrongful conviction of first-degree murder and a subsequent death sentence.
Being transported to death row by bus, Kimble’s fellow prisoners attempt an escape. The pandemonium sends the bus down a ravine and into the path of an oncoming train. Kimble saves a guard, escapes the collision and flees, while the train derails violently as a result of the collision. Senior Deputy U.S. Marshal Samuel Gerard and his colleagues Renfro, Biggs, Newman and Poole arrive at the crash site and begin the search for Kimble.
Meanwhile, Kimble sneaks into a hospital to treat his wounds and alter his appearance. He eludes the authorities and disappears into the sewer system. Gerard follows him, but slips, falls, and drops his weapon. Kimble takes the weapon and points it at Gerard, proclaiming his own innocence; he does not shoot, however. After Kimble runs away, Gerard eventually corners him at the edge of a storm drain over a dam. Kimble leaps into the raging water and escapes.
Kimble returns to Chicago to hunt for the real murderer. Once there, he acquires money from his friend and colleague Dr. Charles Nichols. Posing as a janitor, Kimble enters Cook County Hospital’s prosthetic department to obtain a list of people who had prosthetic arms repaired shortly after his wife’s murder. While there, Kimble realizes that a young patient has been misdiagnosed; Kimble forges new doctor’s orders for the patient, saving his life, but is later confronted by a hospital physician who realizes that Kimble is not who he claims to be.
Following a police lead confirming Kimble’s recent whereabouts, Gerard speculates that Kimble is searching for the one-armed man. While visiting a local courthouse at Chicago City Hall to interview one of the people on his list, Kimble narrowly avoids being apprehended by Gerard and his men and disappears into the midst of a parade. Kimble later breaks into the residence of one of the people on the list, a former police officer named Fredrick Sykes. Kimble sees a picture of Sykes and recognizes him as his wife’s murderer. Kimble finds that Sykes is employed by a pharmaceutical company, Devlin MacGregor, which is scheduled to release a new drug called Provasic. Kimble investigated the drug in the past and discovered that it caused liver damage, which would have prevented it from being approved by the FDA. Following further research, he deduces that Nichols—who is leading the drug’s development—arranged a cover-up and ordered Sykes to kill him; his wife was not the intended victim.
The Provasic drug is to be presented at a pharmaceutical conference at the Chicago Hilton & Towers Hotel. As Kimble takes an elevated train there to confront Nichols, Sykes appears and attacks him. In the struggle, Sykes shoots a transit cop before being subdued and handcuffed to a pole by Kimble. At the conference, Kimble interrupts Nichols’ speech, confronting him about falsifying medical research and orchestrating the murder of Kimble’s wife. This leads to a fight on the hotel roof before they fall through a skylight.
Having arrived on the scene, Gerard calls out to Kimble that he knows about Nichols’ conspiracy and that Kimble is innocent. Nichols knocks out Renfro, takes his gun, and attempts to shoot Gerard. Kimble attacks Nichols from behind with a pipe, knocking him unconscious and saving Gerard’s life. Kimble surrenders to Gerard, who escorts him out of the hotel. Sykes and Nichols are arrested. Kimble is driven from the crime scene by Gerard with his exoneration now assured.