The ambitious but ill-educated, illusioned, and immature Clyde Griffiths is raised by poor and devoutly religious parents who force him to participate in their street missionary work, and on reaching young adulthood takes low-status jobs as a soda jerk and then as a bellhop at a top Kansas City hotel. There, his more sophisticated colleagues introduce him to alcohol and prostitutes. Clyde enjoys his new lifestyle and becomes infatuated with the mercenary Hortense Briggs, who exploits this characteristic of Clyde by compelling him to buy her an expensive jacket in exchange for love, even though she clearly does not want him to be her partner. Hortense instead wants another person named Sparser, and this is clear to Clyde who is immediately and extremely jealous, but Hortense repeatedly reassures Clyde that she loves him, though she really wants him just for the jacket. Later, Clyde's life changes dramatically when Sparser, driving a stolen vehicle with everybody inside (including Clyde's colleagues), runs over a little girl and kills her, and then, trying to flee from the police, crashes into an object, and everybody inside but Sparser and his partner are still conscious and flee. This cycle of unfortunate events is bound to repeat later in the story with Clyde and another girl, later resulting in the novel being a tragedy. Clyde flees Kansas City, and while working as bellboy at an exclusive club in Chicago, he meets his wealthy uncle Samuel Griffiths, the owner of a shirt-collar factory in the fictional Lycurgus, New York. Samuel, feeling guilt for neglecting his poor relations, offers to help Clyde if he will come to Lycurgus. When Clyde does so he gives him first a menial, then a supervisory job at the collar factory, while not accepting him into the Griffiths' upper-class social circle.
It is made clear to Clyde that as a Griffiths, he should not consort with the working people of Lycurgus, and specifically with the women under his supervision. As he is not taken up socially by the Griffiths' set, he suffers loneliness. In this position, he is attracted to Roberta Alden, a poor and innocent farm girl working in his department, who falls in love with him. Clyde initially enjoys the clandestine relationship (forbidden by factory rules); he ultimately persuades her to have sex with him rather than lose him, and makes her pregnant. Meanwhile the elegant Sondra Finchley, daughter of a Lycurgus factory owner, takes an interest in Clyde primarily to spite his cousin Gilbert, with whom she is on bad terms. Clyde's engaging manner makes him popular among the young smart set and provides him with opportunities to develop a relationship with Sondra. The pregnant Roberta expects him to marry her, but Clyde dreams instead of marrying Sondra.
Having unsuccessfully attempted to procure an abortion for Roberta, Clyde procrastinates while his relationship with Sondra matures. When he realizes that he has a genuine chance to marry Sondra, and after Roberta threatens to reveal their relationship unless he marries her, Clyde reluctantly devises a plan to murder Roberta in an ostensible boating accident, having seen a news report of such a case.
Clyde takes Roberta on a row boat on Big Bittern Lake in upstate New York and rows to a remote area. As he speaks to her regarding the end of their relationship, Roberta moves towards him, and he unintentionally strikes her in the face with his camera, stunning her and capsizing the boat, rendering it all an accident instead of a murder. Roberta, unable to swim, drowns while Clyde, unwilling to save her, swims to shore. The narrative does imply (without stating explicitly) 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. A sensational trial before an unsympathetic and prejudiced audience of mostly religious conservative farmers ensues; despite a vigorous (and untruthful) defense mounted by two lawyers hired by his uncle, Clyde is convicted, sentenced to death, and (an appeal having failed) is executed by electric chair. The jailhouse scenes and the correspondence between Clyde and his mother stand out as exemplars of pathos in modern literature.