In the end, the pope won out over “Game of Thrones.”

It was the second day of rehearsal of “Shear Madness,” a zany little whodunit that happens to be the longest-running play in America but is about to open in New York City for the first time, and the cast and the directing team were mulling over their scripts in a Midtown Manhattan office.

This, however, was no ordinary table read. It more closely resembled a late night comedy writers’ room, as actors frantically flipped through their pages, spitballing pop culture punch lines. After a voracious back-and-forth about Winterfell, the lowbrow popemobile, Peter Dinklage and gaudy queens, the director, Bruce Jordan, decided that a quip about the pope’s dress was the way to go.

Started by Mr. Jordan and Marilyn Abrams at a dinner theater in Lake George, N.Y., in 1978, ”Shear Madness” was intended to be a summer one-off. But it thrived on audience interaction and a relentless pace, and eventually spread to Boston, then Philadelphia, then Chicago, and on to Barcelona, Buenos Aires, Kuala Lumpur, and Seoul.

But despite being seen by millions across the globe, and grossing $232 million, the show has never made it to New York — until now.

“Shear Madness” begins its Off Broadway previews on Thursday at New World Stages, driven by a team that believes that the show’s populist, winking attitude and word of mouth will win over the theater world’s biggest city — with or without sniffy critics and highbrow audiences. (“Sheer Torture,” read the Washington Post reviewin 1987.)

“Lots of people apologize for entertaining people, which I think is ridiculous,” said Jeremy Kushnier, a Broadway veteran (“Jesus Christ Superstar,” “Footloose”) who most recently played Iago in “Othello” at the Pittsburgh Public Theater. “Not everybody wants to go into the theater and then walk out feeling worse than they did when they walked in.”

In “Shear Madness,” Mr. Kushnier portrays the seemingly innocuous Eddie, who steps into a barbershop with a briefcase full of secrets, and has to defend himself when a murder is committed upstairs. The show unfolds like a game of “Clue” — it’s up to the audience to use the various pieces of onstage evidence to name a lead suspect.

The script revels in being contemporary and anachronistic at the same time. It is set on the date and in the city of the performance — the New York version will take place at a barbershop on 50th Street and Ninth Avenue, a block away from the theater — and the actors brainstormed topical punch lines to throw in every day. (Expect to hear Ben Carson jokes galore in the coming weeks.)

But the show more closely resembles a laugh-tracked sitcom of yesteryear, like “The King of Queens,” rife with campy caricatures and double entendres. “We call it a fizzy burlesque because the jokes are big, the characters are big,” Mr. Jordan said.

“Shear Madness” was born after Mr. Jordan and Ms. Abrams bonded over their love of Noël Coward while working on another play together. He stumbled upon a British translation of a murder mystery by the German playwright Paul Pörtner called “Scherenschnitt,” which relied on audience members to help piece the clues together.

“There was nothing like it,” Mr. Jordan said. With the help of a friend, they translated it word for word and took the new production, now titled “Shear Madness,” to Boston.

The goal all along was to make it to Manhattan. “We were going to run there for eight weeks, make back our money, and move to New York,” Ms. Abrams said. Instead, they got sidetracked by success. By the time producers in Philadelphia and Washington came calling, Mr. Jordan and Ms. Abrams knew they had a winning formula for a certain-sized city. New York could wait.

When The New York Times wrote about Boston’s “Shear Madness” for the first timein 1982, it was already running longer than any other play at the time. Thirty-three years later, it still rolls along, eight times a week, at the unabashedly unpretentious Charles Playhouse.

The 200-seat house was largely full on a recent Friday night, the audience howling at jokes at the expense of Medford, a nearby town, and Derek Jeter. The crowd delighted in helping the police collect clues for the investigation, shouting out whenever a character lied about his or her previous actions. Audience participation may no longer be a new gimmick, but this crowd didn’t seem to mind.

The show hasn’t taken off in every location — it fell flat in Los Angeles in 1993, in particular — and New York presents new challenges. What good is a local joke when many theatergoers are tourists, and the Hell’s Kitchen experience is far different from the Park Slope one?

“It’s a lot easier when you’re in a smaller market,” Mr. Jordan acknowledged to the New York actors, while dreaming up an extracurricular organization that a New York police officer would belong to. “When you’re in Milwaukee, the Friday night fish fry, they’ve all done it, it kills.”

Somewhat stumped, the performers cycled through New York touchstones — the Circle Line, Chelsea Piers — before settling tentatively on the gleeful ickiness of the “Gowanus Canal Kayaking Club.”

For actors accustomed to reading straight down the page, “Shear Madness” is like being on a unicycle. They’re not only adding fresh jokes every night, but they must also react swiftly and in character to enthusiastic audience interrogation, as if they were improvising. In fact, there’s a cheat sheet of 73 audience questions at the back of the 150-plus page script that the cast members should be prepared to answer.

“You have to remember the things that you actually did, and then remember the things that you forget, and then know the things you have to then potentially re-remember,” Mr. Kushnier explained.

Early rehearsals consisted of the actors aimlessly searching through their scripts for answers to stray queries.

“I think it took me about a year and a half before I really knew what I was doing,” said Patrick Noonan, the only member of the main cast with “Shear Madness” experience — a lot of it. He’s been with the show on and off in Washington and San Francisco since 1998.

The chaos comes partly from the rapid-fire pace and prop work, but mostly from the unpredictable audience, and the constant recalibrations made nightly, based on its response. In Boston, a John Boehner crying joke was met with stony silence, whereas one about the Texas teenager who was suspended for bringing a clock to school got a roar.

As for that pope joke, which the New York cast worked so hard to develop, it will most likely be scrapped by opening night. “I love trying new stuff, and if it doesn’t work, it’s just between us actors,” Mr. Noonan said.

“People aren’t going to walk out of the theater a better person,” he added, “but they will walk out in a better mood.”