Rusty Griswold (Ed Helms) is now an adult working as a pilot for a low budget airline called Econo-Air, and he shares an awkward relationship with his wife, Debbie (Christina Applegate), and their two sons, the shy and awkward older teenager, James (Skyler Gisondo), and the cruel and obnoxious younger kid, Kevin (Steele Stebbins). The gloating from his friends, Jack (Keegan-Michael Key) and Nancy Peterson (Regina Hall), about a family trip they had in Paris doesn’t help his situation. He desires to relive the fun of his family vacations from his childhood (such as their trip to Vegas, Europe, Walley World, and even staying home for Christmas). These memories prompt him to nix his family’s annual trip to their cabin in Cheboygan, Michigan and instead drive cross country to Walley World, just like he did years before with his parents and sister.
Along the way, the Griswolds make many stops. The first is Memphis, where it’s revealed that the otherwise laid-back Debbie was an extremely promiscuous woman in college called Debbie Do Anything. While staying at a motel, James meets Adena (Catherine Missal), a girl his age that he saw while driving on the highway, but is scared away by Rusty trying to entice her towards him in a very creepy awkward way. In Arkansas, they are led to a supposedly hidden spring by a drifter, but when they realize that it’s a sewage dump, they return to their rental car only to see it broken into, their luggage and cash stolen and graffitied on. They’re then forced to stop in Texas to receive assistance from Rusty’s sister, Audrey (Leslie Mann), and her husband, Stone Crandall (Chris Hemsworth). Rusty begins to suspect tension in his relationship with Debbie due to Stone’s obviously outward sexual behavior and actions, but she dispels his suspicions. Stone walks in on the couple and makes a show of his attractive body.
Spending the following night at an Arizona campsite, Rusty and Debbie go off to have an unsuccessful attempt at sex at the Four Corners, where officers from all four states confront the couple and each other, while James finally asserts himself against Kevin with help from Adena (who also happens to be there). The next morning, after nearly getting killed by a suicidal rafting guide (Charlie Day), who has just been dumped by his fiancée in the Grand Canyon, their rental car runs out of gas in the middle of the desert and explodes, leading Rusty to relent over the miserable trip and walk off alone. After being tailed-down by a seemingly manic truck driver (Norman Reedus) over what was thought to be a derogatory comment left by Kevin earlier in the trip, he instead returns Debbie’s missing wedding ring and gives them a lift to San Francisco, where they spend the night at a bed-and-breakfast run by Rusty’s parents, Clark (Chevy Chase) and Ellen (Beverly D’Angelo), with the intent of flying home to Chicago the next day. It’s there that Rusty and Debbie confront each other about their eroding marriage and decide to start over again.
With some coaxing by Clark the next morning, Rusty borrows Clark’s Wagon Queen Family Truckster and drives Debbie and the boys to Walley World to ride their newest roller coaster, Velociraptor. After spending the entire day waiting in line, they are cut off by Ethan (Ron Livingston), a more successful airline pilot rival of Rusty’s, and his family before the announcement of the park’s closing. A fight breaks out, which the Griswolds win, forcing the other family to flee. The Griswolds finally board the ride, but it stalls halfway up a loop, and they are rescued after several hours. They are brought closer by the experience, and Rusty uses his airline connections to spend a relaxing vacation in Paris alone with Debbie, which ends up with them getting a very uncomfortable seat on the plane, right next to a lavatory. Uncomfortably, Debbie asks and learns that it will be a 12-hour flight.