Approaching the age of fifty, film director Guido Contini (Daniel Day-Lewis) is facing a midlife crisis that is stifling his creativity and leading him into a variety of complicated romantic involvements. As he struggles to write the script for his latest film, Italia, he is forced to balance the numerous formative women in his life, including his wife, Luisa (Marion Cotillard); his mistress, Carla Albanese (Penélope Cruz); his film star muse, Claudia Jenssen (Nicole Kidman); his confidante and costume designer, Lilli La Fleur (Judi Dench); an American fashion journalist, Stephanie (Kate Hudson); a prostitute from his youth, Saraghina (Fergie); and the spirit of his deceased mother, Mamma (Sophia Loren).
Throughout the film, it is slowly revealed that Guido has been traumatized by his strict Catholic childhood, and it is implied he was beaten in boarding school. In present-day, he frequently has visions of his mother, and their love for each other. Guido has not written a word for Italia, although the press, the public, and his crew believe it is complete. Things are further complicated when Guido gets away to a spa retreat, whereupon Carla follows him and they secretly lead a life of love in the musty train station town. Soon, Luisa discovers truths, Claudia admits details, Lilli listens, Saraghina haunts, and Stephanie attempts to woo Guido with her charm.