David Gale (Spacey) is a prisoner on death row in Texas. With only a few days to his execution, his lawyer negotiates a half million-dollar fee to tell his story to Bitsey Bloom (Winslet), a journalist from a major news magazine known for her ability to keep secrets and protect her sources. He tells her the story of how he ended up on death row, revealed to the movie audience through a series of lengthy flashbacks.
Gale is head of the philosophy department at the University of Austin, an author and also an active member of DeathWatch, a group campaigning against capital punishment. He loses a televised debate with the Governor of Texas, when he is unable to point to an example of a demonstrably innocent man being executed.
Gale is married, with a young son he dotes on. But his wife, who is having an affair, spends a lot of time away in Spain. At a graduation party, he encounters Berlin (Rhona Mitra), an attractive female graduate student who had previously tried to entice him into raising her failing grade and had later been expelled from the school. Berlin now corners the inebriated Gale and succeeds in getting him to have rough sex with her. She then falsely accuses Gale of rape. Later, she drops the charges and flees, but the negative publicity costs Gale his career and marriage and earns him a reputation as a rapist for the rest of his life.
Constance Harraway (Linney), a fellow DeathWatch activist, is a close friend, especially after Gale's wife leaves with their son. Gale's wife moves to Spain where the custody laws favor the child's mother and her father is the American ambassador in Madrid. Gale is effectively shut out of his child's life. He has also resorted to taking menial jobs and under the stresses of it all has become an alcoholic.
Harraway is found raped and murdered. She has been suffocated by a plastic bag taped over her head and her hands have been handcuffed behind her back. An autopsy reveals that she had been forced to swallow the handcuffs' key, a psychological torture technique which the movie implies was used by the secret police agency of Communist Romania during the regime of Nicolae Ceauşescu, which Gale and Harraway had both protested against. The physical evidence at the crime scene points to Gale, who is convicted of her rape and murder and is, ironically, sentenced to death.
At this point, after several daily visits from Bitsey Bloom, Gale's story has reached the present. Between visits she has been investigating some areas herself. It becomes clear to Bloom that the details simply do not add up. She is also tailed several times in her car by a figure who turns out to be Dusty Wright (Matt Craven), the alleged one-time lover and full-time DeathWatch activist partner of Harraway.
Wright slips evidence to Bloom that suggests Gale has been framed, implying that the "real" murderer videotaped the crime. Bloom pursues this lead until she finds a tape revealing that Harraway, who was suffering from terminal leukemia, had committed an elaborate suicide to look like murder. She and Wright are both seen on the videotape, showing that they have framed Gale as part of a plan to prove the error of using the death sentence.
Bloom does not find the evidence until the day of Gale's scheduled execution. In a frenzy, she tries to get the evidence to the authorities in time to stop the execution. She arrives at the prison just as the warden announces that the execution has already been carried out. The tape is then released, causing a media and political uproar over the execution of an innocent man.
Later, Dusty receives the fee that Bloom's magazine agreed to pay for the interview, and delivers it to Gale's ex-wife in Spain, along with a postcard from Berlin apologizing for the false rape accusation. His ex-wife looks distraught, knowing Gale told the truth and that she effectively stole their child away from him.
Much later still, a videotape labeled "Off the Record" is delivered to Bloom. This tape picks up at the point where Wright confirmed that Harraway was dead, then continues on to show him stepping aside to allow Gale, also present, and party to the suicide, to caress her head one last time with his hand. It was in doing this that Gale left his fingerprints on Harraway's plastic suffocation bag.
The plot has some parallels with the 1999 Clint Eastwood drama True Crime, but with a different outcome.