The film opens in the early 1970s in front of the Quick Stop Groceries and the Record Rack stores in Leonardo, NJ. A kindly mother leaves a stroller with her toddler son, Bob, in front of the store while she goes inside to buy food. She gives the boy a baseball cap that she puts on his head with the visor turned backwards. Another mother, more foulmouthed and demeaning toward her own toddler, Jay, leaves her stroller in front of the store while she goes into the record store to score drugs. A man walks out & asks her who'll be watching the kids while their mothers are inside. The woman lets loose with a torrent of foul language, laced liberally with the F-word, attacking the man for questioning how she raises her kid. The guy walks away, disgusted The child of the foul-mouthed mother stands up in his stroller and begins to recite the F-word in rhythmic fashion and the scene dissolves to the two boys as young adults; they have grown up to become the foul-mouthed Jay and his taciturn companion, Silent Bob. The duo stand in front of the stores (the Quick Stop is still there but the record store has changed to RST Video) most days and deal drugs. When a couple of teenagers approach them, Jay launches into a rap sales pitch reminiscent of Morris Day & the Time's "Jungle Love". When the younger teen derides the song, Jay grabs him and threatens him. From the video store, Randal Graves appears and tells Jay and Bob to let the kid go and that the Time sucked anyway. Jay tells the two buyers that Randal and his coworker, Dante Hicks, are both a gay couple and that their wedding ceremony was Star Wars-themed. Randal says he'll do something that should've been done long ago: he calls the police. Jay and Bob are arrested after Jay mouths off to the cop.
Jay and Bob go to the comic book store that bears their name to talk to Banky. They've been slapped with a restraining order that forbids them to go to either Quick Stop or RST. Banky tells them both that they shouldn't have to bother selling drugs anymore because of the royalties they received when the comic series they inspired, Bluntman and Chronic, was sold to a major motion picture studio. The two are stunned, saying they didn't know about the deal. Banky tells them both that they should talk to his old business partner, Holden McNeil, who brokered the deal after he'd bought Banky out of his share of the original comic.
The two go to Holden's offices and confront him about the movie. Holden tells them that Banky had lied to them and had brokered the deal, leaving Holden with nothing. He also says that the buzz on the internet is that the movie will be very profitable. Jay and Bob are both clueless as to the existence of the internet and Holden shows them an example of a forum website where fans and non-fans of Bluntman and Chronic are sharing their views on the unfinished film. Jay and Bob are furious at the negative buzz and make it their mission to go to Hollywood and stop the production of the film.
Without a car, the two decide to hitchhike. After receiving advice from an expert hitchhiker where he tells them to perform sexual favors for rides, the two are picked up by a nun. She throws them both out of her car when Jay suggests that the Rules of the Road require him to pay her with oral sex. Stranded in front of a Mooby's restaurant, they go inside to get something to eat. They find an internet station and launch a foul-mouthed response to their detractors on Moviepoopshoot.com. While they order their food, a beautiful woman, Justice, walks in. Jay is immediately smitten and imagines kissing her to Bon Jovi's "Bad Medicine." After they introduce themselves, they hitch a ride with Justice and her two companions, Chrissy and Sissy. Also joining them is a geeky guy with a guitar, named Brent. Justice tells them that she and her comrades are animal rights activists who travel around the USA freeing animals from medical testing laboratories. After a few minutes, Jay and Bob quickly dispose of Brent when they trick him into falsely admitting he hates animals.
The team arrives at a research facility somewhere in the West. After taping Jay and Bob saying that they are the masterminds behind the liberation of the animals in the facility, Jay and Bob break into the place and start searching. Justice, Sissy and Chrissy also steal into the facility from another entrance and reveal their own plan: they will steal a fortune in diamonds while Jay and Bob are arrested as patsies. The girls are able to slip past most of the security devices, but Chrissy farts and sets off the alarm. They flee in a sports convertible, leaving Jay and Bob behind.
Meanwhile, Jay and Bob have found an orangutan named Suzanne and bring her outside, only to find the local authorities waiting for them. A slew of animals also escapes. Jay and Bob escape in the confusion. One of the cops happens to be a Federal Wildlife Marshal named Willenholly. He takes up pursuit of Jay and Bob, believing that they've kidnapped the monkey.
Jay and Bob make their way toward Hollywood with the inept Willenholly following them. In California, Justice and her friends have cashed in the loot they stole and are living well near the beach. Justice feels tremendous guilt about deceiving Jay and Bob and decides to find them.
Jay and Bob make it to a large dam and are found by Willenholly. They evade him, Willenholly falling off the dam into the river below. Meanwhile, Suzanne is picked up by a car bearing a sign "Critters of Hollywood". Jay, frustrated, asks Bob what they can do now. Bob tries to mime a plan to chase the car that picked up Suzanne but Jay doesn't understand him. Bob finally lets loose a screaming tirade saying he'd seen the sign on the car. The two leave for Los Angeles.
In LA, Jay and Boy find a couple of drug dealers who belong to the same union they do. The guys take them to the studio where Bluntman and Chronic is being filmed. They find the actors who are cast in their roles, knock them out and take their costumes. On the set, they fill in for the actors and begin shooting a scene with the film's villain, Cock Knocker, who bears a huge fist. The shoot is completely disrupted and Jay and Bob find Banky among the entourage. They confront him about selling the rights to their characters without their permission. Though Banky tries to weasel his way out of any responsibility, Bob gives a lengthy reply in proper legalese explaining that they are the obvious inspiration for the main characters and deserve a full share of the movie's profits. Banky agrees.
Also on the set is Justice, who has come to find Jay. Chrissy and Sissy have also caught up with her seeking revenge. The girls battle it out with Justice the victor. However, Justice is still arrested for the theft she participated in. Jay promises to wait for her.
The movie opens & is a success. Banky asks Jay and Bob what they'll do with their share of the royalties. The two realize they can travel across the country and find their detractors from the web and beat them up.