Doug Madsen (Tim Allen), Woody Stevens (John Travolta), Bobby Davis (Martin Lawrence) and Dudley Frank (William H. Macy) are four middle-aged suburban men in Cincinnati who find themselves frustrated with the pace of daily life. Woody is a formerly rich businessman who suddenly finds himself alone and broke. Doug is a dentist who cant connect with his son, and he misses his college glory days when he was called The Golden Knight. Bobby is a plumber who is henpecked by his wife and daughters while trying to follow his dream of writing a plumbing how-to book. Dudley is a computer geek who seeks to find a woman in his life. Their one collective hobby had always been to ride together on motorcycles around the city, though after college that happened less and less often.
When Woody finds out that his marriage is ending in divorce and that he's bankrupt, he suggests they embark on a cross-country road trip west on their bikes to seek adventure. After some hesitation from the other three, the four agree to the trip and set off on their Harley-Davidsons.
The road trip is filled with humorous moments, such as sleeping close together scantily dressed and being found by a policeman (John C. McGinley) who tells them they can be charged with lewd and lascivious behavior, but it turns out that he is only teasing: he is actually jealous. Later, when the four go to a small lake, a family on a picnic joins them in the water only to realize the four men are naked. The policeman appears again; he also undresses and joins the four men, who quickly leave.
The fun ends when the four stop at a bar and stumble onto a real motorcycle gang called the Del Fuegos. Del Fuego leader Jack (Ray Liotta) tricks the foursome into a bum motorcycle trade, then tells them they are nothing compared to real bikers, especially Del Fuegos founder Damien Blade, and that they should leave before something else bad happens.
Less than a mile away, Woody stops, disgraced at what just transpired. He tells his friends that he will go back to the bar to retrieve Dudley's bike, but when he gets back there, a courageous Woody cuts the fuel lines on the gang's motorcycles and takes Dudleys bike. He returns to his friends with the bike (to much astonishment) and explains that he simply threatened the gang with legal action. When the Del Fuegos realize what has transpired, provoked by the Wild Hogs riding past the bar again, Jack orders his gang to follow the Wild Hogs. When Jack errantly tosses his cigarette, it hits gasoline on the ground and triggers a chain reaction that blows up the bar. The Del Fuegos swear revenge.
Meanwhile, because of Woodys insistence that they should not stop for any reason, the Wild Hogs run out of gas and have to walk their bikes a long distance until reaching the small town of Madrid, only to discover they have to stay the night to wait for the fuel station to open. The four are first mistaken for actual Del Fuegos and feared, but once the mistake is cleared up, the Madrid Sheriff tells the Wild Hogs that the Del Fuegos terrorize the town yearly and the small police force who received weapons training by playing the video game Doom is unable to do anything about them.
At a chili festival that night, Dudley furthers his interest in Maggie (Marisa Tomei) the owner of the local diner. As he courts her, Bobby comes across two Del Fuegos in town (who have spotted the Wild Hogs and informed Jack). Thinking himself untouchable, because of Woodys previous explanation, Bobby humiliates the two bikers. Under orders from Jack, the two Del Fuegos refuse to do anything and Bobby ends up squirting them with ketchup and mustard. The town praises the Wild Hogs as saviors, considering them a friendly biker gang who can protect them.
Dudley spends the night with Maggie. The next morning, the Del Fuegos arrive en masse and Jack yells to the townspeople that his gang will vandalize the town, starting with the diner, until the Wild Hogs come out to fight. Woody reveals his lie about the biker bar incident, plus his reason to take the trip (his divorce) and his friends are disappointed with his deceit. When the Del Fuegos start to wreck Maggies diner, Dudley goes out to meet them. The rest of the Wild Hogs eventually back up Dudley and a four-on-four fistfight begins between four Del Fuego bikers and the Wild Hogs. Easily outmatched, the Wild Hogs are beaten up, but refuse to stay down and see the diner destroyed. With their dignity on the line, they continue to get up and take punch after punch, much to the amazement and fury of Jack. Just then, the townspeople arrive carrying makeshift weapons to defend their new friends; they demand the Del Fuegos leave the Wild Hogs alone and get out of town. The situation is defused by the arrival of Damien Blade himself (Peter Fonda). Blade chastises Jack and the Del Fuegos for picking on four men and the townspeople, and reveals he actually thought his bar was a dump and explained that he insured the bar for twice what it was worth. We also learn that Jack is Damien's son, and he points out to Jack how he forgot what being out on the open road is about, and that it doesn't involve thuggish behavior and violence. Jack's split-second transformation from the ultimate bully into a guilty-faced momma's boy is almost as priceless as Woody's earlier impersonation of a tough Marlon Brandoesque biker earlier on. The Del Fuegos, feeling guilty, leave and offers a friendly good-bye to the Wild Hogs. In a salute to Fonda's own memorable role in Easy Rider, Blade tells the Wild Hogs that they need to "lose the watches," referring to the Easy Rider scene when, just before departing on their cross-country chopper-born odyssey, Fonda's character takes off his watch and throws it in the dirt.
Bobby and Dougs wives arrive in town, giving Bobby the chance to tell his wife that he dislikes how she controls him, and the two reconcile. Doug impresses his son by telling him of the adventures. Dudley tells Maggie he will return to town soon to enjoy more time with her, and the four head finally continue on to the Pacific coast.
The closing credits include excerpts from a faux episode of Extreme Makeover: Home Edition where the Del Fuegos are given a brand new bar. Jack can barely restrain his emotions as he views it.