The film features two men, Johnny B. and Kamal, aka "the Jerky Boys", two self-described "low-lifes from Queens", who get into trouble with the Mafia when one of their prank calls leads them into a money laundering business. The Jerky Boys discover that their long-loved hometown bar will be torn down unless they stop it.
The film opens in a New York police station as a pair of "low-lifes from Queens" named Johnny B. (Johnny Brennan) and Kamal (Kamal Ahmed) are taken into police custody and interrogated by an NYPD detective named Robert Worzic (Brad Sullivan). Worzic demands to know exactly how the pair got into their situation, so Johnny explains that for the past twenty years, he and Kamal frequently entertained themselves by performing prank calls on the telephone. He brings up an early call where he got his neighbor Brett Weir, the local goody-two-shoes kid, in trouble with his mother by impersonating an angry citizen and claiming that Brett has been spitting and cursing.
One day twenty years later (the beginning of the film's present day), Johnny and Kamal are adults and still performing prank calls, but Johnny's mother Mrs. B (Suzanne Shepherd) demands that they get jobs. Johnny argues that they get fired from everything they try, even though their reason for termination usually stems from their inability to not insult people over radios and intercoms. Mrs. B compares them to Brett Weir (James Lorinz), who has grown to live a very successful life and now owns his own house, and tells them to get out of the house and job-hunt.
Johnny and Kamal decide to head to Mickey's, their local bar, and knock back a few drinks placed on their sizable tab. They happen to meet Brett, who buys them drinks and brags that he's on his way to a meeting at a fancy restaurant. Curious, Johnny calls Brett's new friends at the restaurant as "Frank Rizzo" and tells the people on the other end (in no polite terms) that "his men" Johnny and Kamal have just gotten in from Chicago and need to be cared for. Unbeknownst to the pair, Brett's friends are actually the local Mafia run by Ernie Lazzaro (Alan Arkin), who is confused and bewildered at "Rizzo" and his vulgarity but nonetheless gives the boys a limousine ride and a fully comped meal.
Feeling that they have stumbled onto a good job, Johnny calls again as "Rizzo" the next day and demands another good time for him and Kamal. This time, Lazzaro and his right-hand man Tony Scarboni (Vincent Pastore) introduce the pair to the many Mafia leaders and officials on their payroll. They are given money as an advance on their first assignment: beat up Mickey so the mob can take over his bar and tear it down. At this point, the boys realize what they're in and that they're in deep. As they try (and fail) to convince Mickey (Alan North) to lay low, Brett recognizes them and reveals to Lazzaro that they're not mobsters at all. Scarboni's men Geno (Brian Tarantina) and Sonny (Peter Appel) later grab Johnny and Kamal and takes them to a hot dog-processing plant so that Scarboni can run them through the grinder as punishment. Using their vocal talents, the boys distract their captors and escape. Johnny and Kamal lead Scarboni and his men through the city, crashing a local concert, stealing a cab, and wrecking a nightclub magic show along the way. They eventually make it back to Johnny's house in Queens, only to get arrested by Worzic for all the trouble they caused.
Returning to the present situation, Johnny and Kamal insist to Worzic that everything was just a big misunderstanding and try to tell him of Lazzaro's many rackets in the city. Worzic, however, only cares about "Frank Rizzo" (who apparently is an actual Mafia boss that he wants arrested) and throws the boys in a jail cell. They are each given one phone call: Johnny calls his mother, who is threatened by Scarboni to tell them where he is, while Kamal calls a local demolition crew. They are later released on bail and picked up by Scarboni's men so that they can take them to Lazzaro and Scarboni, who are now fitting Mrs. B with cement shoes. Johnny insists that "Frank Rizzo" can set everything straight and calls his house, where he had previously set up a tape-recording of "Rizzo" to play on the answering machine. Though it seems to work well enough to make Lazzaro brag about his operation, Brett sees through the deception and the rest of the mob chase after the boys and Mrs. B.
Barely making it back to Queens, Johnny and Kamal immediately call Worzic and tells them that they have taped evidence to incriminate Lazzaro. Instead, the detective is revealed to be on the take (explaining his prior refusal to help) and joins Lazzaro in chasing the boys, but they are distracted when Lazzaro recognizes the next-door neighbor Uncle Freddie (William Hickey) as a Mafia boss from long ago. This gives the boys the chance to escape downtown and call every news outlet they can think of with their evidence that exposes Lazzaro. They credit "Frank Rizzo" as the informant, who in turn credits Johnny and Kamal as "The Jerky Boys".
Lazzaro, Scarboni, Worzic, and all their accomplices are arrested, while Johnny and Kamal are made heroes and given a cushy office job in a high-rise building. Not surprisingly, they start off by prank calling the White House and demanding to know who's in charge. Meanwhile, Brett Weir has just gotten out of prison after making a deal with prosecutors, only to see his house getting torn down by the demolition crew that the Jerky Boys had called earlier.
- Johnny — (Himself) one of the two prank callers.
- Kamal — himself, one of the two prank callers.
- Ernie Lazzaro — (Alan Arkin) a powerful mob boss who the prank callers get tangled up with.
- Tony Scarboni — (Vincent Pastore) Lazarro's right-hand man.
- Geno — (Brian Tarantina) Scarboni's bumbling underling.
- Sonny — (Peter Appel) Scarboni's bumbling underling.
- Robert Worzic — (Brad Sullivan) a detective who is trying to bring a fictional "Frank Rizzo" down
- Brett Weir — (James Lorinz) Johnny's weaselly mob-connected neighbor. A victim to the Jerky Boys.
- Mrs. B — (Suzanne Shepherd) Johnny's long-suffering mother.
- Uncle Freddy - (William Hickey) Johnny's Neighbor, seemingly a harmless old kook but really an old-time mob boss
- Mickey — (Alan North) Owns the bar Johnny B. and Kamal frequent.
- Construction Foreman — (Joe Lisi) a construction worker, who fires Johnny and Kamal.
- Burger Bob Customer — (Ron Ostrow) a customer ordering lunch at Burger Bob's drive through.
- Band Manager — (Ozzy Osbourne) band manager for Helmet.
- Henry Bogdan — (Himself) one of the four members of Helmet.
- Rob Echeverria — (Himself) one of the four members of Helmet.
- Page Hamilton — (Himself) one of the four members of Helmet.
- John Stanier — (Himself) one of the four members of Helmet.