In The Patron Saint of Liars, Rose is a young wife of three years who concludes she married by mistake, that she misinterpreted teenage lust as a sign from God. Newly pregnant and unable to continue a life with a man she doesn't love, Rose decides to leave. She abandons her quiet, inoffensive husband and their life at the southern California seaside of the 1960s.

Rose plots to give up the baby for adoption, never telling her husband. And to punish herself, she will also give up the mother she adores, the one person she really loves. Leaving without notice, she drives east to Kentucky and soon realizes that any new life will be a deception and she will be a liar for the rest of her life.

Rose's destination is the sanctuary of St. Elizabeth's Home for Unwed Mothers in Habit, Kentucky. St. Elizabeth's is a refuge but also a place of liars and "leavers," for all of the girls who come will leave, and most will lie about where they've been and what has happened. Unlike the other young women, Rose is married but chooses to tell no one. She plans to wait out her pregnancy, give over the baby to adoption, and then move on.

But St. Elizabeth's keeps Rose for years. In the once elegant Hotel Louisa, the home is near the site of a healing spring run dry, a spring that still exerts a little magic. Rose learns to cook for the girls who come and go and befriends the saintly Sister Evangeline, who knows people's troubles and sees their futures.

Rose decides to keep her baby and marries Son, the groundskeeper, and once again begins a small life with a man she doesn't love. Her daughter Cecelia, or Sissy, grows up at St. Elizabeth's among the nuns, a devoted father, and successive waves of unwed mothers. Sissy longs for her mother's love and attention and wonders about her past.

Most of the odd and troubled characters fascinate and confound us. In the end, Rose surprises us one more time, and Sissy grows up, showing herself neither a liar nor a "leaver."