The play covers a period of twenty-five years in the lives of mostly upper-middle-class East Coast characters. It centers on Nina Leeds, a passionate, tormented woman whose fiancé was killed in World War I and who spends the remainder of her life searching for an always-elusive happiness.

This is a very long play, lasting over five hours in performance. The story is not especially complex, and the length of the play derives from O'Neill's revival of two theatrical devices that had fallen out of use for nearly a century: the soliloquy, in which a character alone on the stage speaks his or her thoughts aloud, and the aside, which enables characters to reveal their thoughts to the audience but not to the other characters on stage. These devices, which O'Neill employed at length, enabled the playwright to probe deeply into his characters' motivations. The soliloquies and asides reveal the discrepancies between what the characters say and do, and what they really feel.

Strange Interlude was a controversial play because it dealt openly with such topics as adultery and abortion. Although it was rarely revived in the early 2000s, it was generally regarded as the first of O'Neill's works in which he revealed his full power as a dramatist.