Imogene Duncan, played by Kristen Wiig, is a struggling playwright who has hit rock bottom after her career fails miserably. Her boyfriend, Peter, breaks up with her, and Imogene becomes despondent. In a desperate attempt to win him back, she fakes a suicide attempt, hoping that he will come to her rescue.
However, her plan backfires when she is taken into custody by the hospital. Her family is contacted, and her estranged mother, Zelda, played by Annette Bening, comes to take care of her. Imogene is forced to return to her childhood home in Ocean City, New Jersey, where she is reunited with her family, including her younger brother Ralph, played by Christopher Fitzgerald.
Imogene finds it hard to adjust to life back home and is constantly at odds with her mother. Zelda, a compulsive gambler, spends most of her time at the local casino. Imogene also meets a young man named Lee, played by Darren Criss, who is renting a room in their house. Imogene enlists Lee's help in tracking down her ex-boyfriend and regaining control of her life.
Through her misadventures in Ocean City, Imogene learns to come to terms with the mistakes she has made in the past and begins to mend her relationships with her family. Girl Most Likely is a heartwarming comedy that explores the trials and tribulations of a woman trying to find her place in the world.