Are You There God? It's Me, Margaret explores the sensitive topics of religion and adolescence from the eyes of an 11-year-old part Christian-part Jewish girl Margaret Simon (Abby Ryder Fortson). Margaret's family relocates from New York to New Jersey, meaning she has to make new friends.
Margaret's mother, Barbara Simon (Rachel McAdams), who is Christian and Jewish her father, Herb Simon (Benny Safdie), raised her without any religious affiliation, making her feel out of place. Nonetheless, Margaret believes in God and prays to Him, beginning with, 'Are You There God? It's Me, Margaret.'
Settling well in the new suburban home, Margaret befriends Nancy, Gretchen and Janie, and the four form a secret club called Pre-Teen Sensations. They explore different topics of their young developing bodies, including menstruation, boob growth and teen dating. The girls are eager to mature, as shown in the trailer- a hilarious scene where they exercise to increase their busts while chanting, 'We must, we must, we must increase our bust!'
Apart from Margaret's maturing challenges, the film tackles a tarnished relationship between Barbara and her parents, Mary and Paul Hutchins, because of choosing to raise her child outside the Christian faith. Margaret's paternal grandmother Sylvia Simon, portrayed by Kathy Bates actively takes part in the child's life, even taking her to Rosh Hashanah services, leading her to embrace Judaism.