A low-level marijuana dealer living in Denver, David Clark, is robbed of his money and stash, some of which he owes to his wealthy drug supplier, Brad Gurdlinger. After David is brought to him, Gurdlinger forces him to smuggle marijuana from Mexico as a solution to clear his debt. Realizing that one man attempting to get through customs is too suspicious, he hires a stripper neighbor stage-named Rose, a runaway 19-year-old petty thief named Casey, and his awkward 18-year-old neighbor Kenny to pose as a bogus family called the “Millers”. When the Millers reach the compound, they find out that the amount of marijuana they were picking up is not “a smidge” as Gurdlinger had informed them, but actually two tons. Because of the extra load of the marijuana on the RV, one of the radiator hoses breaks while going up a steep incline. A family they had encountered at the border called the Fitzgeralds, consisting of Don, Edie, and Melissa, catch up to them and tow the Millers’ RV to a repair shop. On the trip to the shop, David learns that Don Fitzgerald is a DEA agent after finding his badge and gun in the glove compartment.
The marijuana turns out to be stolen from Pablo Chacon’s cartel where Gurdlinger had David pose as an agent of Chacon. The next day, when the Millers head to the shop to pick up the RV, Chacon and his henchman, One-Eye, are waiting for them and prepare to execute the family. They immediately tell Chacon that they aren’t a real family and that they didn’t know they were stealing from him. Rose is given a chance to prove that she is a stripper by dancing, and when she gets close, turns a steam vent onto Chacon. The Millers then escape in the RV, with Kenny behind the wheel. Due to Kenny’s erratic driving, the RV veers off the highway and a tarantula, from in a bowl of fruit given to them when they picked up the marijuana, crawls up Kenny’s leg and bites his testicle.