Following the violent collapse of his financial world, a distraught businessman kills his estranged wife and flees with his two young daughters, Victoria and Lilly, with the intent of killing them and then himself. Their escape ends at a remote, decrepit cabin in the woods, but before he can finish his tragic intent, a mysterious entity intervenes. The man is killed, and the girls are left alone in the wild, where they remain lost and feral for five years, surviving inexplicably with the help of an unseen presence they affectionately call "Mama".

Rescued by search parties sponsored by their Uncle Lucas, the traumatized and animalistic children are placed in his care and that of his girlfriend, Annabel. As they attempt to reintroduce the girls to a normal life and bond with them, Annabel faces the challenge of motherhood to two deeply disturbed children. Concurrently, the family finds themselves under the watchful eye of Dr. Dreyfuss, a psychiatrist interested in the girls' case for his own professional reasons. The harmonious domestic transition is marred, however, as it becomes clear that the entity known as "Mama" has followed the girls from the cabin to their new home, and its intentions might not be as benign as the children believe.