Mildred is a widow, Gena Rowlands living with her rebellious, irresponsible twentysomething daughter Annie in Salt Lake City. After a fight, Annie leaves to live with her boyfriend, leaving Mildred alone for the first time in her life. Her wayward neighbor Monica, Marisa Tomei knocks on Mildred's door, begging her to watch her young son J.J. so she can go to her work shift. Monica has kicked her abusive husband Frankie, David Thornton out of their house.
Mildred agrees to babysit and promises to be there for Monica whenever she needs. She forms a close bond with J.J., and he starts calling her "Auntie Mildred." Mildred fills the hours with simple but tender routines: reading to him, taking him to the park, and teaching him history using her encyclopedias. At Thanksgiving, Mildred invites Monica and J.J. to dinner, along with her own yuppie son Ethan and his wife Jeannie, Bridgette Wilson-Sampras. Jeannie is perturbed by Monica's brash behavior and cursing, while Ethan and Mildred themselves seem emotionally distant. Ethan even suggests Mildred move to San Francisco with him and Jeannie.
Mildred spends Christmas with Monica and J.J., babysits on New Year's Eve, and on Valentine's Day Frankie returns to Monica's house. She quietly listens to his pleas but does not open the door. Monica arranges a night out with Mildred, taking her to a pub where she introduces her to her friend Big Tommy, Gérard Depardieu, a truck driver who expresses quiet interest in Mildred. After the evening, Monica leaves without telling Mildred, and Big Tommy gives her a ride home.
Later, Mildred travels to San Francisco to visit Ethan and Jeannie. He invites her to live on the top floor of their luxurious Bay Area home and reveals that Jeannie is pregnant, but Mildred declines the offer, which enrages him. When she returns home, she finds that Monica and Frankie have reconciled, and J.J. begins spending more time with his father, leaving Mildred feeling more isolated and adrift.
One night, Annie returns to Mildred's life and asks if she can come back home, saying she has a job and is applying to college. But Mildred has decided to move, having sold the house and telling Annie she must be out by the end of the month. She goes on a date with Big Tommy and confesses she doesn't know where she will move to.
As Monica helps Mildred pack, she shares how Frankie has improved as a husband, though she senses Mildred's distance. Later, Frankie brings J.J. over to talk privately; the boy offers a drawing and thanks Mildred for taking care of him before finally saying goodbye. Annie eventually drives Mildred to the airport, and Mildred refuses to reveal her destination, keeping it a secret.
