The film traces the sexual and emotional confusion of two men from their Amherst College days in the fifties through the Kennedy sixties, up to the Vietnam era. Jonathan (Jack Nicholson), a successful tax attorney and Sandy (Art Garfunkel), a physician, personify two extremes of self-delusion and self-aggrandizement: Jonathan makes the mistake of thinking sex is love, and embarks on a lifetime of sexual conquest; Sandy dedicates himself to the pursuit on an idealized woman and the dreamy spiritual completeness to be found therein. In Bobbie (Ann-Margret) Jonathan finds a partner whose masochism compliments his selfishness and emotional ambivalence. Jonathan does not want her to hold a job, but neither does he like the fact that she spends all day in bed sleeping, or watching TV. Sandy falls in love with his first collage romance, Susan (Candice Bergen); they marry and have children. But Sandy is haunted by the fear that he was too hasty, even though he and Susan lead a happy domestic life and strive to reinvigorate their sex life by making love "in all seven rooms" of their apartment. With Jonathan's help, he enters into an affair with Cindy (Cynthia O'Neal), a tough professional woman who turns Sandy off because she is too overbearing.

When Jack Nicholson would get ready to play his nude scenes, he'd prepare everyone on set by warning, "Here comes Big Steve!"

Jonathan:
Is this an ultimatum? Answer me, you ball-busting, castrating, son of a cunt bitch! Is this an ultimatum or not?