Jeff Gaffney (Zach Galifianakis) works at the McDowell-Burton International (MBI) as Human Resources and lives with his wife, Karen (Isla Fisher) and two children, who are away at sleep-away camp. After the couple buys a new house, located at the Cul-De-Sac under the proprietors of Dan & Meg Craverston (Matt Walsh and Maribeth Monroe), Karen alerts Jeff of the new neighbors, the Joneses couple, Tim and Natalie (Jon Hamm and Gal Gadot), and invites them over to her house to introduce themselves, surprising Jeff upon arriving home from the office.Karen learns that Tim is an accomplished travel writer whose hobbies include blowing glass and Natalie is a social media consultant, cooking blogger and heroine to Sri Lankan orphans. Feeling unconvinced about Natalie, Karen follows her to the mall hoping to discover what she's doing, but Natalie catches Karen in the dressing room. Here, Natalie confronts her, realizing that Karen must be following her. Meanwhile, Tim invites Jeff to the Chinese restaurant to eat, but Jeff feels that getting drunk with a snake wine and being bitten by a severed snake head is not the way to make a friend and that true friendship is having an indoor skydiving experience together.Meanwhile Tim and Natalia break into MBI HQ & find that a suspicious email has been sent using Jeff's computer to an international arms dealer called scorpion. Back at their house, Jeff accidentally breaks the glass sculpture made by Tim that was given to them, revealing a bug among the shards. The couple now realize that they have been spied upon the whole time and they decide to sneak to the Joneses' house to find the spying device. Inside the room, they discover that Jeff and the MBI employees are being targeted by the Joneses. However, Jeff, mistaking an item for a pen, accidentally stuns Karen with the pen gun and they narrowly escape just as the Joneses arrive at the house. Natalie notices the pen gun on the floor and that it has been used, suspecting that Gaffneys might have broken into their house.The Gaffneys arrange a meeting with MBI advisor Carl Pronger (Kevin Dunn) to explain the details about the Joneses. But before Carl can disclose further details, he is killed by a sniper who also attacks the Gaffneys. They are rescued by the Joneses and a chase and shootout ensues, killing the masked motorcycle riders. The Gaffneys now learn that the Joneses are the secret agents. Upon entering the house, the Joneses narrowly escape just as a bomb blows up the house. It is revealed that the international arms dealer calling himself "the Scorpion" (Patton Oswalt) is trying to take down the Joneses and then kidnap the Craverstons, who are planning to sell the microchips - which could be used to weaken the U.S. missile defense system. Dan reveals that he is the one who used Jeff's computer to email the arms dealer. Jeff then accepts the offer through the Scorpion's phone call, arranging the meeting with his wife at the hotel and takes Dan's cover name, "Rascal Flatts", to deliver the microchips.With the Joneses at their back, the Scorpion, whom Jeff helped to relieve the stress by letting him hold the small red ball at the MBI years ago, blows Jeff's cover. With their cover blown, Tim radios for back-up but they pull out due to collateral damage that will be done to the public. Jeff also blows the Scorpion's cover, whose real name is Bruce Springstine. When the Gaffneys and the Joneses are held captive, Karen is able to pass a knife to Natalie by making out with her as a distraction, giving the Joneses an opportunity to kill Bruce's men. They all escape by jumping off the window just as Bruce opens the briefcase containing the chips that blows the bomb, killing him.One summer later, Jeff and Karen visit the Hazim's Cafe in Marrakesh, where the Joneses used to date. They meet the Joneses, who reveal that they have left the agency. However, when four men, who might be working for another agency to track them down wearing fezzes, are seen looking at them, the Joneses engage in a gunfight with the four men, not showing the actual occurrence.