In 1968, Deloris Wilson is a young, but less-than-serious Catholic school student, much to the chagrin of her teacher nuns. In 1992, the adult Deloris is a lounge singer in Reno, Nevada, performing as “Deloris Van Cartier”. After Deloris witnesses her gangster boyfriend Vince LaRocca execute an informant, police lieutenant Eddie Souther places her in witness protection. She is brought to Saint Katherine’s Parish, a convent in a run-down San Francisco neighborhood. Deloris initially objects, but relents, and goes along with it.
The Reverend Mother, the head nun of the St. Katherine’s, also objects to taking Deloris in, but Monsignor O’Hara, the priest of the parrish, convinces her to go along with it, as the police will pay the failing convent a good sum of money. Disguised as “Sister Mary Clarence”, Deloris struggles with the simplistic and rigid convent life, but starts to befriend the other nuns, including the perky heavyset Sister Mary Patrick, the shy young Sister Mary Robert, and the elderly deadpan Sister Mary Lazarus. One night, after a poorly attended Sunday Mass, with a lackluster performance from the convent choir, led by Master Lazarus, Deloris sneaks out to a bar, followed by Mary Patrick and Mary Robert. They are caught by the Reverend Mother, and Deloris is forced to join the struggling choir. With her singing experience, Deloris is elected their new director, and she works to transform the choir.
At the next Sunday Mass, Deloris leads the much-improved choir in a traditional performance of “Hail Holy Queen”, before shifting into a gospel and rock-and-roll interpretation. Although the Reverend Mother is infuriated, Monsignor O’Hara congratulates the choir’s unorthodox performance for attracting new people to the service. Convinced by Deloris, he allows the nuns to clean up the church and the neighborhood. Their singing, and efforts to revitalize the neighborhood attract media attention, and the parish starts to thrive.
Souther chastises Deloris for nearly being exposed on national television, as Vince has placed a bounty on her head. Deloris assures him, she’ll try to keep a lower profile, and Souther attends a mass. The choir continues to amaze parishioners and visitors with a rendition of “My Guy” – rewritten as “My God”.
O’Hara informs the convent that Pope John Paul II, having heard of the choir’s success, will visit the church himself. Deloris tells the Reverend Mother that Vince’s upcoming trial means she will soon leave, and the Reverend Mother reveals she has resigned, believing she is no longer of use to the convent, as her authority was unintentionally undermined. Deloris tries to convince her to stay and keep things going, but the Reverend mother believes herself too old-fashioned and uncapable.
Souther discovers a corrupt detective in his own department has given Deloris’ location to Vince, and rushes to San Francisco to warn Deloris, but she is kidnapped by Vince’s men. Afterwards, the Reverend Mother reveals Deloris’ identity to the nuns, and they decide to go after her, requesting a helicopter pilot to fly them to Reno. There, Vince orders his men to kill Deloris, but they are reluctant to shoot her while she is dressed as a nun. Arriving at Vince’s casino, the nuns find Deloris after she escapes from Vince’s men. They become trapped in the casino lounge, and Deloris prepares to sacrifice herself. Before Vince can shoot her, Souther arrives and arrests Vince and his men.
Thanking Deloris for what she has done, the Reverend Mother decides to remain at the convent. Returning to San Francisco, the choir, led by Deloris, sing “I Will Follow Him” to a packed audience in Saint Katherine’s, receiving a standing ovation from all, including the Pope, O’Hara and Souther. Deloris continues to guide and coach the choir as a singing tour.