At a bar in Philadelphia during 1999, a man named Santos anxiously grips a briefcase in a secluded booth. In a shocking turn of events, he rushes out, only to be ruthlessly followed and murdered by the bartender in a dark alleyway. Meanwhile, Jamie and Sukie, portrayed by Margaret Qualley and Beanie Feldstein respectively, find their relationship taking a nosedive due to Jamie's betrayal. After Sukie ends things and kicks Jamie out, Jamie learns that her friend Marian, played by Geraldine Viswanathan, is plotting a getaway to Tallahassee, Florida, and she jumps at the chance to tag along.
They opt for a one-way car service, only to find themselves mistakenly with a vehicle already reserved for someone else's trip to Tallahassee. This blunder sets off a chain of unpredictable events involving a trio of criminals—Arliss, Flint, and The Chief, depicted by Colman Domingo. As they come to collect their ride, they discover that Jamie and Marian are unknowingly involved in a web of illegal activities along with the mix-up.
While Marian aspires to head straight to Tallahassee, Jamie urges her to take scenic detours, trying to spice things up by hitting up lesbian bars for casual encounters. Although Marian prefers to immerse herself in Henry James' The Europeans, Jamie’s relentless teasing gradually nudges her to embrace the adventure. Upon their arrival in Florida, fate intervenes as they suffer a flat tire, leading them to discover the briefcase that Santos had been holding—alongside an unsettling basket containing his head and a suspicious smoky substance.
Pursued by Arliss and Flint, a wild chase ensues as a soccer team, who had caught wind of Jamie and Marian's escapade, inadvertently complicates their pursuit. When the pair checks into a hotel using Jamie's credit card, the criminals promptly learn of their whereabouts. In the spirit of seizing the moment, Jamie convinces Marian to explore their own desires further, leading to an intimate encounter. But their tranquility is short-lived; moments after Jamie's release, Arliss and Flint burst into their room, reclaiming the briefcase and abducting both women at gunpoint.
In a gritty backroom of a dog racing track, the Chief briefs everyone about the bizarre contents of the briefcase—a collection of dildos crafted from the plaster casts of renowned men’s genitals, including that of Senator Gary Channel, played by Matt Damon, who is terrified of the implications this revelation would have for his public image. In a frantic turn of events, Flint turns on his accomplices, resulting in chaos. Jamie and Marian decide to leverage the situation by blackmailing Channel upon discovering that this infamous dildo was used by Jamie that very morning and inadvertently left behind.
Meanwhile, Sukie, acting as a police officer, is on her way to Tallahassee, tipped off by Jamie. Jamie and Marian orchestrate a meeting with Channel at a lesbian bar, trading the infamous dildo for a hefty sum—one million dollars. However, as they try to make their exit, Sukie intercepts them and Channel makes a reckless move to eliminate the threat. Sukie manages to shoot Channel, leaving him severely wounded but still alive, as his reputation teeters on the edge of disgrace with newspapers eager to publish stories about his dubious connections.
In a subsequent meeting with Marian's aunt at their hotel, Jamie breezily reveals their plans to head to Massachusetts where same-sex marriage is legal. As their fun-filled journey continues, a bellhop rushes to return a forgotten bag, giving them one last twist—a pair of plaster casts of the very dildos that had caused so much chaos, modeled after Senator Channel's anatomy.
