In the vibrant city of Denver, David Clark, portrayed by Jason Sudeikis, is a small-time marijuana dealer who finds himself entangled in a troubling situation after being robbed of his supply. Faced with the threat of paying off a debt to the ruthless Brad Gurdlinger, played by a deceptive acquaintance, David sees no option but to comply with Gurdlinger’s dangerous demands. Tasked with smuggling an outrageous quantity of marijuana from Mexico, David realizes the gravity of his predicament—this mission is anything but trivial.
To dilute suspicion and navigate customs more effectively, David asserts that he needs help. Enter his unsuspecting neighbors: Rose, a stripper who uses her stage name, portrayed by Jennifer Aniston; Casey, a mischievous runaway with a penchant for trouble; and Kenny, a naive teenager recently left behind by his family. Together, they form an unusual yet determined family unit known as the "Millers," each taking on roles—Rose as the “wife,” Kenny as the “son,” and Casey in the role of the “daughter.”
Arriving at Gurdlinger’s compound, the Millers are shocked to discover that the marijuana haul is not just a manageable amount but a whopping 2 tons! Their journey back to the border is fraught with challenges, relying on a mix of clever tactics and sheer luck to evade capture. However, disaster strikes when one of the RV's radiator hoses bursts, leaving the Millers stranded on their journey. Just then, they are fortuitously rescued by the Fitzgerald family—Don, Edie, and their daughter Melissa—who are blissfully unaware of the Millers' illicit activities as they enjoy their own RV vacation.
As the Millers and Fitzgeralds travel together, young Kenny finds himself smitten with Melissa, leading to a series of awkward and comedic romantic misadventures as Casey and Rose try to navigate the tension their unconventional family poses. Unbeknownst to the Millers, more trouble is brewing behind the scenes. Gurdlinger’s betrayal is revealed; he has no intention of helping David and plans to rob the marijuana from the terrifying cartel boss, Pablo Chacon.
The following day, while collecting their RV from a repair shop, the Millers come face-to-face with Chacon and his menace of a henchman, One-Eye. In a daring bid to escape, Rose channels her inner performer and distracts Chacon with impressive dance moves, inadvertently causing chaos that allows the Millers a narrow escape. The escape, however, is hardly smooth sailing as an unexpected tarantula from their stash in Mexico bites Kenny, leading to a chaotic sequence that has the group racing to the hospital while juggling the escalating pressure of their original mission.
As Kenny suffers an intense allergic reaction, David's resolve hardens, leading to a hefty agreement with Gurdlinger that involves a massive payout of $500,000—not to mention a very tight timeline. With Kenny still recovering and confined to a wheelchair, tensions flare when David inadvertently reveals the unequal financial arrangement between him and the crew, sparking a falling out that sees Rose, Casey, and Kenny abandoning David for the local carnival—a decision fueled by hurt and betrayal.
Yet, remorse drives David back to the carnival in search of redemptive forgiveness. Surprisingly, despite their initial hesitation, the trio agrees to reunite, but their journey is abruptly interrupted by One-Eye, only to be saved by Don who comes to the rescue. The chaos escalates when Chacon appears, leading to a dramatic confrontation where the Millers must rely on quick thinking and teamwork to survive. With the 4th of July fireworks acting as a backdrop, David and Kenny seize their moment to defeat their enemies.
However, just when things seem to settle, a bombshell revelation from Gurdlinger shatters David's hopes—his arrest was always part of the plan. The DEA intervenes, taking David into custody thanks to a tip-off, leaving him facing the cold reality of betrayal. Meanwhile, Don assures David that he and his witnesses will be placed in protective custody until Gurdlinger and Chacon are dealt with.
The Millers, now entangled in a new and unexpected chapter, find themselves relocated to a suburban neighborhood with a surprising twist—a backyard filled with flourishing marijuana plants, hinting that their adventures are far from over.
