Loosely based on serial killer Henry Lee Lucas, the film follows Henry and his roommate Otis who Henry introduces to murdering randomly selected people. The killing spree depicted in the film starts after Otis' sister Becky comes to stay with them. The people they kill are strangers and in one particularly gruesome attack, kill all three members of a family during a home invasion. Henry lacks compassion in everything he does and isn't the kind to leave behind witnesses - of any kind.

On November 22, 1963, president John F. Kennedy is assassinated in Dallas. Lee Harvey Oswald is arrested for the crime and subsequently shot by Jack Ruby, supposedly avenging the president's death. An investigation concludes that Lee Harvey Oswald and Jack Ruby acted alone in their respective crimes, but Louisiana district attorney Jim Garrison is skeptical. Assembling a trusted group of people, Garrison conducts his own investigation, bringing about backlash from powerful government and political figures.

A quadriplegic ex-homicide detective and his female partner try to track down a serial killer who is terrorizing New York City.