An American Tragedy is the story of Clyde Griffiths, a young man raised by penniless religious fanatics. Clyde falls into a life of crime, flees his hometown, and becomes a foreman in the factory of his wealthy uncle. His uncle, though, does not permit him access to rarified social circles. Isolated and forbidden from interacting with the workers, Clyde begins clandestine romances with a poor worker and with a bored socialite. Eventually he murders the pregnant worker in an attempt to join high society, but he is caught and executed.
Ambitious but ill-educated, naïve, and immature Clyde Griffiths is raised by poor and devoutly religious parents to help in their street missionary work. As a young adult, Clyde must, to help support his family, take menial jobs as a soda jerk, then a bellhop at a prestigious Kansas City hotel. There, his more sophisticated colleagues introduce him to bouts of social drinking and sex with some of the hotel's female guests and with prostitutes.
Enjoying his new lifestyle, Clyde becomes infatuated with Hortense Briggs, who inveigles Clyde into buying her an expensive jacket. When Clyde learns Hortense desires his colleague Sparser, not himself, as a lover, he becomes jealous. Hortense repeatedly tells Clyde that she loves him while getting him to buy her the jacket (for which they are overcharged by a stereotypically greedy Jewish shopkeeper).
Clyde's life changes dramatically when Sparser, driving Clyde, Hortense and other friends back from a secluded rendezvous in the country in a stolen car, hits a little girl and kills her. Fleeing from the police at high speed, Sparser crashes the car. Everyone but Sparser and his partner flee the scene of the crime. Clyde leaves Kansas City, fearing prosecution as an accessory to Sparser's crimes. This pattern of personal irresponsibility and panicked decision-making in Clyde's life recurs in the story, culminating in the central tragedy of the novel.
While working as a bellboy at an exclusive club in Chicago, he meets his wealthy uncle Samuel Griffiths, the owner of a shirt-collar factory in the fictional city of Lycurgus, New York. Samuel, feeling guilt for neglecting his poor relations, offers to help Clyde if he will come to Lycurgus. When Clyde accepts the offer, his uncle gives Clyde a menial job at the factory, in which Clyde makes a very good showing. After that, Samuel Griffiths gives his nephew Clyde a minor supervisory job at the collar factory's offices.
Samuel Griffiths' son Gilbert, Clyde's immediate supervisor, makes it clear to Clyde that as a Griffiths, he should not consort with the working people of Lycurgus, and specifically not with the women under his supervision. As Clyde has no close friends in Lycurgus, he becomes lonely. Emotionally vulnerable, Clyde is drawn to Roberta Alden, a poor and innocent farm girl working in his office, who falls in love with him. Clyde secretly courts Roberta, ultimately persuading her to have sex with him rather than lose him, and makes her pregnant.
At the same time this is happening, elegant young socialite Sondra Finchley, daughter of another Lycurgus factory owner, takes an interest in Clyde despite his cousin Gilbert's efforts to keep them apart. Clyde's engaging manner makes him popular among the young smart set of Lycurgus, he and Sondra become close, and he courts her as well as Roberta. Roberta expects Clyde to marry her to avert the shame of an unwed pregnancy, but Clyde now dreams instead of marrying Sondra.
Having failed to procure an abortion for Roberta, Clyde doesn't give her more than desultory help with living expenses while his relationship with Sondra matures. When Roberta threatens to reveal her relationship with Clyde unless he marries her, he reluctantly plans to murder her by drowning while they go boating, having read a local newspaper report of a similar boating accident.
Clyde takes Roberta out in a canoe on Big Moose Lake in upstate New York and rows to a secluded bay. As he speaks to her regarding the end of their relationship, Roberta moves towards him, and he unintentionally strikes her in the face with a camera, stunning her and accidentally capsizing the boat. Roberta, unable to swim, drowns while Clyde, unwilling to save her, swims to shore. The narrative implies that the blow was accidental, but the trail of circumstantial evidence left by the panicky and guilt-ridden Clyde points to murder.
The local authorities are eager to convict Clyde, to the point of manufacturing additional evidence against him, although he repeatedly incriminates himself with his confused and contradictory testimony. Clyde has a sensational trial before an unsympathetic and prejudiced jury of mostly religious conservative farmers. Despite a vigorous (and untruthful) defense by two lawyers hired by his uncle, Clyde is convicted, sentenced to death, and after an appeal is executed by electric chair. The jailhouse scenes and correspondence between Clyde and his mother are exemplars of pathos in modern literature.