Outside an inn in Amiens, Edmondo leads students and girls in chorus about the pleasures of youth, while des Grieux enters, despondent (“Tra voi belle”). The others mock him, suggesting he is coming off an ill-starred affair. Just then, a carriage arrives containing Manon, her brother Lescaut, and Geronte, the Treasurer General. Des Grieux falls madly in love with her (“Donna non vidi mai”) and Manon shares his infatuation. When he discovers she is on her way to a convent at the order of her father, he asks that she meet him later. Meanwhile, Geronte convinces Lescaut to help him kidnap Manon. He agrees, dazzled by the old man’s wealth. Edmondo overhears and quickly warns des Grieux, who convinces Manon to escape with him in Geronte’s carriage. Lescaut is not concerned, as he believes Geronte’s wealth will lure Manon away from des Grieux.
Having left the impoverished des Grieux, Manon is now Geronte’s mistress. Lescaut visits her at Geronte’s house, where Manon complains that her new wealth is stultifying and that Geronte is too old and dull. She thinks of des Grieux and the simple life they shared. (“In quelle trine morbide”) Lescaut announces that des Grieux has gotten rich gambling and runs off to find him. Geronte enters with musicians and a dancing master for Manon’s entertainment. After they leave des Grieux enters and reproaches Manon, but she quickly charms away his anger. (“Tu, tu, amore, tu”) Geronte discovers the lovers together and, after being mocked by Manon, leaves in disgrace. Lescaut rushes back to warn them of Geronte, who is coming back with the police. Despite the need to escape, Manon cannot surrender her jewels, and attempts to gather them up in her cloak. The police burst in, find the jewels, and arrest Manon for theft.
Manon is being held in Le Havre among prostitutes and is set to be deported to Louisiana. Lescaut and des Grieux arrive with a plan to liberate Manon. Lescaut bribes a guard and des Grieux rushes off to speak with Manon through her bars. The escape plan falls through and Manon is led out on roll call. The crowd flings filthy comments at Manon as her name is called, but Lescaut arouses their compassion for his sister. As the girls are led onto the ship, a devastated des Grieux begs the captain to let him stow away, no matter how undignified his work must be. (“No! No! pazzo son!”) The captain is moved by des Grieux sadness and allows him on board.
Fleeing New Orleans, the victims of intrigue and jealousy, Manon and des Grieux wander a vast desert in search of sanctuary. As night falls, Manon feels herself dying and sends des Grieux away in search of shelter. Alone, she laments her destruction and her poisonous beauty. (“Sola, perduta, abbandonata”) Des Grieux returns to find her on the verge of death. He collapses to the ground, overcome with grief.