As the overture ends, Benny Southstreet, Nicely-Nicely Johnson, and Rusty Charlie discuss the day’s races ("Fugue for Tinhorns"). A Mission Band enters ("Follow the Fold"), led by Miss Sarah Brown. Sarah denounces the vices of gamblers and exits.

Lieutenant Brannigan enters, looking to break up Nathan Detroit’s gambling ring. Nathan arrives without noticing him and quickly puts his foot in his mouth. Brannigan leaves and the gamblers brainstorm where to hold the crap game ("The Oldest Established"). The Biltmore Garage seems ideal but requires a $1,000 fee. Nathan decides to swindle Sky Masterson (a big-time player in town) out of the money needed. As the Mission Band approaches ("Follow the Fold – Reprise"), Nathan gets Sky to bet that Sky can convince any doll to go with him to Havana. Nathan chooses Miss Sarah.

Sky visits the Save-a-Soul Mission and pretends to be a sinner, but Sarah sees through his lies. After switching tactics to get her to agree to attend dinner with him, which she refuses, Sky presses Sarah to tell him what type of guy she would be interested in ("I’ll Know"). Sky kisses Sarah; she slaps him.

At the Hot Box, Adelaide and the girls perform their big number (A Bushel and a Peck). Afterwards, Adelaide explains to Nathan that her lingering cold may be psychological, caused by the fact that Nathan won’t marry her ("Adelaide’s Lament"). Benny tells Nicely that Nathan should start lining up the game because he’s sure to win. Realizing that Nathan is with Adelaide, the two gamblers bemoan the “worldwide weakness” of men ("Guys and Dolls").

Back at the Mission, General Cartwright, the head of the Save-a-Soul Mission, arrives and tells them the Mission will close. Sky enters and bargains with the General, inviting her to the upcoming prayer meeting, where Sarah guarantees one dozen sinners in attendance. In doing so, she has accepted Sky’s dinner invitation. On the street again, Nathan still doesn’t have a location for the game.

Lt. Brannigan arrives and Benny convinces the lieutenant that they are gathered for a bachelor dinner in honor of Nathan’s wedding (forcing Nathan to agree to elope with Adelaide). The Mission Band enters without Sarah. Realizing he’s lost the bet and can’t get a place for the game, Nathan faints.

In Havana, Sarah is enjoying a few too many of the drinks Sky ordered and explains to him how she’s feeling ("If I Were A Bell"). Suddenly having real emotions for Sarah, Sky realizes it’s best to head back to New York. Arriving outside the Mission, Sky reveals something about himself to Sarah ("I’ve Never Been In Love Before"). They are greeted by Arvide Abernathy and the Mission Band out looking for sinners. They’re interrupted by a stream of gamblers, led by Nathan, pouring out of the Mission just before Brannigan and the police arrive. Sky tells Sarah he had nothing to do with the game, but she is disillusioned.

The next night at the Hot Box, Sky is sitting in the audience looking dejected. After learning from Nicely that Nathan will not elope with her, Adelaide complains to him that Nathan won’t change his ways and again laments her condition ("Adelaide’s Second Lament").

Meanwhile, Arvide presses Sarah to be honest about her feelings for Sky. Sky arrives and reminds Sarah he promised to fill the prayer meeting with sinners.

In the sewers, Big Julie refuses to the let the game end until he is back in the black. Sky tries to convince the gamblers to attend the prayer meeting and bets them one thousand dollars each against their souls. If he wins, they go to the meeting ("Luck Be a Lady"). Sky wins.

Above ground, Nathan runs into Adelaide, and agrees to leave immediately to elope but remembers his debt to Sky and abruptly rescinds his offer. She storms off enraged. The gamblers stream into the Mission for the prayer meeting. General Cartwright asks for the men to share their sins with the group ("Sit Down You’re Rockin’ the Boat"). Nathan apologizes to Sarah for his bet with Sky, but explains that no harm was done as he won the bet. The meeting concludes ("The Guys Follow the Fold"). Later, Sarah and Adelaide console each other and decide to try a new approach to love ("Marry the Man Today").

Nathan and Adelaide’s wedding day arrives. The Mission Band enters and we discover Sky Masterson playing the drum in full Mission uniform. He and Sarah are married. Arvide agrees to marry Nathan and Adelaide at the Mission and our story ends ("The Happy Ending").