Two best friends, Thelma, a submissive housewife, and Louise, a tough and independent waitress, set out on a weekend getaway from their monotonous lives in Arkansas. As they drive through the country in Louise's 1966 Ford Thunderbird convertible, Thelma's excitement about their freedom quickly reaches a peak. Their trip takes a dark turn when they stop at a roadside bar, and Thelma, naive and overly trusting, faces an attempted rape by a local man. Louise comes to her friend's rescue, and in the chaos that follows, the situation escalates to violence, leaving the man dead. Shocked and panicked by their actions, Thelma and Louise flee the scene, beginning a cross-country escape from the law.

As the women travel further from home, they undergo significant personal transformations, particularly Thelma, who evolves from her initially passive character into a self-assured and resilient woman. With detectives on their trail, led by a sympathetic police investigator who tries to piece together their story, Thelma and Louise are forced to make difficult decisions at every turn. Their journey is marked by both empowerment and desperation, as they encounter various characters across the American Southwest who shape their path in unforeseen ways. The bond between the two women deepens as they share a sense of sisterhood and defiance against the circumstances that brought them together on this path.