Clark Griswold works in the food preservative industry, and has invented a long-life food preservative, earning him a large bonus check from Frank Shirley. To celebrate, he announces to his family that he is taking them on vacation. Part of the reason for the trip is for Clark and Ellen to renew their wedding vows. Excitement wanes, however, when Clark says they are headed to Las Vegas. His wife, Ellen, and teenage daughter, Audrey, have their doubts, as Las Vegas is not known for its family-friendly atmosphere, while teenage son Rusty appears to be more enthusiastic.
Upon arriving in Vegas, the family embarks upon a series of misadventures. The Griswolds attend a Siegfried & Roy show, and they also visit Cousin Eddie, the husband of Ellen’s cousin Catherine. Eddie and his family now live in the desert just north of Las Vegas, on what used to be a hydrogen-bomb test site. While on a group tour of the Hoover Dam led by guide Arty, Clark leaves the group after accidentally creating a leak in the dam’s inside walkways, and is forced to climb the scaffolding to the very top of the dam to get out, because his cries for help cannot be heard over the roaring water. The next night, they are surprised to find tickets to a Wayne Newton concert have been delivered to their hotel room, along with a dress for Ellen. They go to the concert, only to realize that Newton had sent the dress. While singing, he brings Ellen up on stage to sing with him, and visits at their table.
The next day, the family agrees to an “alone day” and are left to their own devices. Clark goes to a casino and becomes addicted to gambling, usually losing to a snide blackjack dealer named Marty, who enjoys Clark’s humiliation. Rusty gets a fake ID from a Frank Sinatra look-alike and becomes a winning high roller, taking on the pseudonym Nick Pappagiorgio. Audrey starts hanging out with Eddie’s free-spirited and gorgeous exotic dancer daughter Vicki and her friends. Ellen begins spending time with Wayne Newton, who has feelings for her.
Clark gambles away the family’s $22,600 bank account, leading a furious Ellen and the kids to desert him. Rusty goes off gambling for cars, and wins four, while Audrey goes to a strip club with Vicki and gets a job as a go-go dancer. Eddie — who has money buried in his front yard — tries to come to Clark’s rescue in return for everything the Griswolds have done for him and his family over the years. Clark and Eddie go to a local casino to get their money back, but Clark ends up gambling away Eddie’s money too, causing him to reevaluate his behavior. Clark then realizes he no longer cares about getting his money back, but needs to get his family back.
Clark then gathers up his family from around Vegas and they gamble their last two dollars on a game of keno. They sit next to an elderly man who compliments Clark on his family, and hints that he has been lonely all of his life. Out of sympathy, Clark tells the man to consider himself part of the Griswold family for the night. The man happily accepts Clark’s offer, and both parties begin the game. At first, the Griswolds are optimistic, but as they realize they have already lost the game, they sit together in silence. Suddenly, the man next to them ecstatically declares that he has won the game. In his burst of joy, he suddenly begins to slip in and out of consciousness while Ellen sends Rusty for help. He revives long enough to whisper a message to Clark, before dropping his winning ticket and lapsing one final time.
Clark, confused, tells Ellen that the man said “take the ticket.” When the casino security guards and paramedics arrive, they declare the man officially dead. They tell the Griswolds his name was Mr. Ellis. As Mr. Ellis is carried away, a janitor approaches with a carpet cleaner, heading straight for the winning ticket on the floor. Though it appears Clark is going to allow it to be lost, at the last second, he slides the ticket out of the carpet cleaner’s path. With their newfound winnings, Clark and Ellen renew their wedding vows.
Afterwards, Clark gives Eddie $5,000 to repay his kindness. They all drive home in the four cars Rusty won on the slot machines: a red Dodge Viper, a maroon Ford Mustang, a black Hummer H1, and a white Ford Aspire.