Doug and Tracy are on the brink of their wedding day, but complications arise when Tracy's parents, Sid (Jeffrey Tambor) and Linda (Sondra Currie), express their disapproval of Doug, played by Justin Bartha. Just five hours before the ceremony, Tracy receives a distressing call from Doug's friend Phil, who informs her that they can't locate Doug.
Two days prior to the wedding: Doug, excited to celebrate his impending marriage to Tracy (Sasha Barrese), decides to head to Las Vegas with his close friends. The group includes Phil (played by Bradley Cooper), a teacher; Stu (Ed Helms), a dentist; and Tracy's quirky brother Alan (played by Zach Galifianakis), who struggles with social ineptitude and ADHD. Despite Doug's reservations about the trip, especially with wedding preparations underway, Tracy insists they go, as Alan has been eagerly waiting for too long.
Alan, well-known for his gambling prowess and previous run-ins with the law, isn't meant to be too close to children or places like Chuck E. Cheese. Tracy warns Doug to keep Alan in check, ensuring he doesn't overindulge. The group's dynamic becomes evident as they depart in Sid's luxury vintage Mercedes-Benz W111, making their way to a Caesars Palace hotel villa, which they book for a staggering $4,200 a night.
As they toast to their Las Vegas adventure on the hotel rooftop, Stu reveals plans to propose to his girlfriend, Melissa, upon returning, holding a ring he saved from World War II. The following morning, when Phil, Stu, and Alan wake up, confusion sets in as they discover Doug is missing. The suite is in disarray: a tiger occupies the bathroom, a chicken roams the living area, and a baby is found concealed in a closet.
Their search for Doug leads them to shocking discoveries, including Doug's mattress seen impaled on a statue outside Caesars Palace. A hospital tag hanging from Phil signals a troubling night, prompting the trio to visit a hospital where Dr. Valsh (Matt Walsh) reveals they were drugged, leading to their memory loss. Their investigation unveils that the previous night included a hasty marriage between Stu and a stripper named Jade (Heather Graham), and they find themselves entangled with gangsters on the prowl for someone.
Amid frenzied encounters with the law and unexpected surprises, like a wild tiger and a mysterious figure named Chow (Ken Jeong), they eventually race against time to find Doug before the wedding. Through unexpected twists and unplanned antics, the men manage to navigate through the chaos, culminating in an epic chase that results in Doug being located in an odd predicament atop the hotel.
As fate would have it, the group arrives just in time for the wedding, with Doug revealing he woke up with $80,000 worth of poker chips in his pockets. In a turn of events, Stu finally stands up to his overbearing girlfriend Melissa and breaks up with her at the reception. As the celebrations wind down, Alan discovers a digital camera that holds photographic evidence of their wild night. Together, they decide to relive their chaotic adventure before choosing to delete the memories forever, each hoping to never repeat such a misadventure again.
