The film begins in the early 1970s outside the Quick Stop Groceries and the Record Rack in Leonardo, NJ. A kind-hearted mother leaves her toddler son, Bob, in a stroller while she quickly runs inside to purchase some food, adorning him with a backwards baseball cap. In stark contrast, another mother, who is both foul-mouthed and derogatory towards her son, Jay, leaves him outside as she heads into the record store to obtain drugs. A man passing by questions her about who is watching the children, prompting her to unleash a stream of explicit language, berating him for intruding on her parenting choices. As the man departs in disgust, young Jay stands up in his stroller, rhythmically repeating the F-word, and the scene transitions to the two boys as adults, now embodying the brash Jay and the reticent Silent Bob. They spend their days outside the stores—now featuring the Quick Stop and RST Video—selling drugs.
When a couple of teenagers approach, Jay enthusiastically launches into a rap-style sales pitch reminiscent of Morris Day & the Time’s "Jungle Love." After one of the teens ridicules the song, Jay, in a fit of rage, threatens him. This draws the attention of Randal Graves from RST Video, who advises them to let the kid go, humorously declaring that the Time "sucked anyway." In a comical twist, Jay claims that Randal and his partner Dante Hicks are in a gay relationship, complete with a Star Wars-themed wedding. Randal decides to step up and calls the police, leading to Jay and Bob’s arrest after Jay continues to act out in defiance.
With a restraining order now prohibiting them from returning to their old hangouts, Jay and Bob head to their comic book store where they meet Banky. He reveals that they should no longer need to sell drugs due to the royalties from their comic-inspired series, Bluntman and Chronic, being sold to a major film studio. Shocked to learn about the deal, Jay and Bob confront Holden McNeil, Banky’s ex-partner, who tells them that he brokered the deal and left them high and dry. Holden informs them that the internet buzz around the movie is highly positive, a concept that Jay and Bob are oblivious to. When they discover the negative feedback online, they make it their mission to travel to Hollywood to halt production.
Lacking transportation, they decide to hitchhike, taking unorthodox advice from a so-called expert who suggests they engage in sexual favors for rides. Their first ride comes from a nun, who promptly ejects them from the vehicle after Jay makes a distasteful suggestion. Stranded outside a Mooby’s restaurant, they find an internet station and unleash a profane retaliation against their critics on Moviepoopshoot.com. While ordering food, Jay sulks over the entrance of the captivating Justice, who captures his attention instantly, leading him to fantasize about her while Bon Jovi’s "Bad Medicine" plays in his mind. After introductions, they hitch a ride with Justice and her friends, Chrissy and Sissy, along with a rather nerdy guitarist named Brent. Justice reveals that they are animal rights activists on a mission to liberate animals from research facilities, prompting Jay and Bob to remove Brent from the equation under false pretenses.
The group makes their way to a research facility out West. While Jay and Bob tape a declaration of their supposed masterminding over the animals’ liberation, Justice and her friends sneak in with their own plan to steal diamonds, leaving Jay and Bob looking like the criminals when things go awry due to a mishap involving Chrissy. The ruckus draws law enforcement, allowing Jay and Bob to escape just as they are discovered with an orangutan named Suzanne. Their luck runs out when the authorities catch up with them during the chaos, specifically a Federal Wildlife Marshal named Willenholly, who believes they have kidnapped the monkey.
With Willenholly hot on their tail, Jay and Bob navigate towards Hollywood, while Justice, burdened by guilt over her deception, decides to track them down. Their journey leads them to a large dam where they once again encounter the relentless Willenholly, who falls into the river below during a high-tension sequence. Meanwhile, Suzanne finds herself in a vehicle advertising "Critters of Hollywood," prompting Jay to seethe with frustration over their situation. They manage to get to Los Angeles, where they align with familiar drug dealers who help them infiltrate the set of Bluntman and Chronic. In a hilarious turn of events, they knock out the actors cast in their roles and don their costumes, unexpectedly walking onto set to film a scene with the villain, Cock Knocker.
In this whirlwind of excitement, they finally confront Banky, who attempts to shirk responsibility for selling their characters’ rights. However, Bob astounds everyone with a well-researched response, detailing their rightful claim to a piece of the movie’s profits. Banky reluctantly agrees to share the rights, and the long-lost Justice reunites with Jay amidst chaos as Chrissy and Sissy pursue revenge against her for outsmarting them earlier.
As the movie finally debuts to great acclaim, Banky queries Jay and Bob about their plans for the royalties. Recognizing the opportunity before them, they devise a plan to track down everyone who has insulted them on the internet and teach them a lesson.
