A low-level marijuana dealer David Clark living in Denver 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 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, hiding in a bowl of fruit given to them when they picked up the marijuana, crawls up Kenny’s leg and bites his testicle.
As Kenny has a severe allergic reaction to the bite, the Millers head to the hospital. This further delays the delivery of the drugs, but David renegotiates with Gurdlinger for a fee of $500,000 on the condition that it arrives that night after mentioning on how he encountered Pablo Chacon. When Kenny is finally released, David rushes him to the RV in a wheelchair and accidentally tips him over. In the ensuing argument, David inadvertently reveals how much he is getting paid, in comparison to how little he offered to pay each of the others. Casey, Rose, and Kenny are left in disgust by the revelation, and so David leaves them at the local carnival.
Shortly after leaving, David regrets abandoning them after hearing “Waterfalls” by TLC on the radio and returns to the carnival, begging them to come back with him. On their way to the RV, they encounter Edie and Melissa. One-Eye discovers them and is about to shoot everyone, but Don comes out of his camper and subdues him. Chacon then comes around the corner with Melissa held at gunpoint and is about to kill them all, but is momentarily distracted by the 4th of July fireworks. David and Kenny subdue him. Don arrests Chacon, but lets the Millers leave.
David delivers the drugs to Gurdlinger, who tells him he’s late and that their deal is off, but then admits that he had never intended to pay at all. DEA agents crash into the room, arresting Gurdlinger. The agent in charge is Don who tells David that he will have to be in the witness protection program until the trial of Gurdlinger and Chacon. He then adds that anyone that was a witness to the crime will be in protection and David smiles. The Millers are then seen together in a suburban house, with several marijuana plants growing in the garden.