It is set in Harry Hope's decidedly downmarket Greenwich Village saloon and rooming house, in 1912. The patrons, who are all men except for three women who are prostitutes, are all dead-end alcoholics who spend every possible moment seeking oblivion in each others' company and trying to con or wheedle free drinks from Harry and the bartenders. They tend to focus much of their anticipation on the semi-regular visits of the salesman Theodore Hickman, known to them as Hickey. When Hickey finishes a tour of his business territory, which is apparently a wide expanse of the East Coast, he typically turns up at the saloon and starts the party. He buys drinks for everyone, regales them with jokes and stories, and goes on a bender of several days until his money runs out. As the play opens, the regulars are expecting Hickey to turn up soon and plan to throw Harry a surprise birthday party. The entire first act introduces the various characters and shows them bickering amongst each other, showing just how drunk and delusional they are, all the while waiting for the arrival of Hickey.
When Hickey finally arrives, his behavior throws the other characters into turmoil. He insists, with as much charisma as ever, but now lumped together with the zeal of a recent convert, that he sees life clearly now as never before, because he is sober. He hectors his former drinking companions that they are meaninglessly clinging to "pipe dreams" of some kind of positive change in their lives, while continuing to drown their sorrows exactly as before. (This is true; the ex-cop and carny hustler tell each other they will ask for their old jobs back on the police force or with the circus, the bartender says he will marry his prostitute girlfriend, etc., with seemingly no chance of any of this coming to pass. One character is even nicknamed Jimmy Tomorrow for his constant protestations.) Hickey wants the characters to cast away their delusions and embrace the hopelessness of their fates. He takes on this task with a near-maniacal fervor. How he goes about his mission, how the other characters respond, and their efforts to find out what has wrought this change in Hickey, take over four hours to resolve. Eventually, after most of the characters briefly leave the bar intending to show Hickey that they actually intend to accomplish their dreams, they all return and are even more upset with Hickey. Hickey, who had earlier told the other characters that his wife had died and that she was murdered, admits that he actually killed her. The police arrive, apparently called by Hickey himself, and Hickey justifies the murder in a dramatic monologue, saying that he did it out of love for her. The other characters conclude that Hickey is insane. Almost everyone remains at the bar. At the end of the play, the youngest character, Don, kills himself.