Doug Madsen (Allen), Woody Stevens (Travolta), Bobby Davis (Lawrence) and Dudley Frank (Macy) are four middle-aged suburban men in Cincinnati who find themselves frustrated with the pace of daily life and lack of adventure. When Woody finds out his wife is divorcing him and leaving him bankrupt, he suggests going on a motorcycle road trip to California.
After the first day's ride, the men lose their tent when Dudley accidentally throws lighter fluid onto the burning tent (thinking it was water). They are forced to all sleep on an air mattress that was spared because Bobby was too slow to blow it up and get it in the tent when they made camp.
The next morning the men encounter a gay highway patrolman (John C. McGinley) who is jealous of them on their trip and "threatens" to charge them with lewd behavior. The men go on and stop at a lake where they go skinny dipping. They are interrupted by a family who stop to swim, and seeing them, leaves horrified. The Wild Hogs are suddenly joined by the same policeman from earlier, who joins the four naked men, which makes them leave. Stopping for fuel and food at a roadside bar, they meet the Del Fuego gang, headed by the tough biker Jack (Ray Liotta) who recognizes the four men as "posers" and takes Dudley's bike. After riding a short distance away, Woody says they should go back and get Dudley's bike. The others refuse, so Woody walks back alone, steals the bike and cuts the fuel lines on the gang's bikes. He quickly drives back to the Wild Hogs, claiming that all he did was threaten to sue the Del Fuegos. The group continues on towards the Pacific.
The Del Fuegos realize what has transpired and try to go after the Wild Hogs, but after their bikes stall, Jack carelessly throws his cigerette onto the line of fluid from where Woody cut the gas lines of the bikes. This causes a chain reaction that blows up the bar.
Because Woody is hesitant to stop for gas after the explosion, the Wild Hogs end up running out of gas. The four end up in Madrid, New Mexico where they are mistaken for members of the Del Fuego group when they quickly grab pitchers of beer they haven't ordered and start guzzling them. Recovering from their thirst, they learn the Del Fuegos regularly terrorize the town, but the police force, which has very little training and no guns, can't do anything.
The four men re-evaluate their lives, especially when Doug, Woody, and Bobby do a "bull-slap" which ends up being painful for two of them and Dudley falls for Maggie (Marisa Tomei), the owner of the local diner.
Eventually, the four men are spotted and the Del Fuegos come to get their revenge, but Bobby, believing that they are safe because of what Woody told them, squirts the two men with ketchup and mustard. The two Del Fuego scouts do not fight, because Jack told them not to hurt the Wild Hogs until he arrived. The Wild Hogs are proclaimed heroes.
The next day, the entire team of Del Fuegos shows up in Madrid. Woody reveals what happened at the Del Fuego bar and the truth behind his need to take the trip, upsetting the others. After the Del Fuegos threaten to burn Maggie's diner, Dudley stands up to the gang, but is captured. The others join Dudley, with Doug declaring that they aren't going to run, but are going to fight. They are easliy outmatched by the Del Fuegos and are beat up badly, holding up against them to keep them busy. The townspeople arrive and threaten the Del Fuegos, when Damien Blade (Peter Fonda), Jack's father and the founder of the Del Fuegos, arrives. Blade tells Jack that the bar was nothing but an insurance scam, and orders his son to leave town.
Doug and Bobby's wives arrive, and the two finally learn to relate to their families. The Wild Hogs reach the West coast soon after. During the credits, the Del Fuegos get a new bar after the Wild Hogs contacted Extreme Makeover: Home Edition to build it.