Tammy (Melissa McCarthy) is not young, but her life is getting more and more bleak. An accident made her lose her car, and then she was fired by her boss at work. The successive blows and setbacks made her frustrated. When she wanted to seek warmth and comfort from her husband, she found that her husband had a lover. What made Tammy collapse was that the lover lived next door to their house. Life has reached a dead end, and Tammy feels desperate. Just when she is in despair, her grandmother Parr (Susan Sarandon) comes to Tammy. However, Parr's arrival did not bring happiness to Tammy, because Parr is an alcoholic and rude old lady. Parr asked Tammy to take her to travel to Niagara Falls, and the two embarked on a journey that was destined not to be peaceful.