Sebastian Maniscalco looks annoyed. Irritated even. But there’s no need to worry: That’s his natural look — his wife says he has a mean resting face.

Counterintuitive for a professional comedian, maybe, but Maniscalco has capitalized on his face — and his irritability — to become one of the most successful stand-ups in the business. He sold out four shows at Madison Square Garden in January, breaking a record for highest-grossing comedy event in North America, and was the fifth highest-paid stand-up in 2019. He’s made four popular specials, published a memoir (“Stay Hungry”) last year and hosted the MTV Video Music Awards in August.

His fans include Jerry Seinfeld, who has featured Maniscalco twice on “Comedians in Cars Getting Coffee.” On the first appearance, in 2016, Seinfeld introduced his guest by saying: “This guy just makes me laugh in so many different ways. He looks funny, he moves funny, he talks funny.”

Picture a suave cartoon character. His big, expressive eyes bulge as he relates his bewildered disgust with human behavior. He throws his body around onstage, pantomiming the characters he’s describing with animated physicality. Always dressed to the nines in his specials, which have titles like “Aren’t You Embarrassed?,” he mines humor from the perspective of a fish out of water in modern society.

“I always have an internal conversation,” he said. “Like the guy next to me was biting his fingernails — it’s killing me. I think I have this thing called misophonia. Like, my wife gets in the car, she eats an apple — the bite of the apple — I want to fly out of the car.”

Now the Chicago-born comic, 46, is returning to an old dream: serious acting. His first big get was a role in “Green Book,” which won an Academy Award for best picture earlier this year. His next part is a small but important one in Martin Scorsese’s gangster requiem, “The Irishman.”

“I do Oscars or I just don’t work,” he joked.

Maniscalco’s character, Joseph “Crazy Joe” Gallo — a real mid-century mobster — doesn’t show up until roughly two hours into the film, but he makes quite an entrance. With long sideburns, slicked-back hair and an entourage, he storms in as a loud and violent problem for Joe Pesci and Robert De Niro.

At a nightclub where, ironically, they’re all watching a comedian perform, Maniscalco explicitly tells De Niro to get out, and walks away. It does not end well.

But it couldn’t get much better for a middle-class kid from the suburbs of Chicago with an accent thicker than Bolognese. Maniscalco was named after his grandfather, Sebastiano, a barber from Sicily. When the comedian’s father, Salvo, came to America in his teens, he carried on the family trade. He ran his own hair salon, Stage Door — eventually expanding to two more: Luigi and Salvo Hair Studio, and Sebastiano’s.

“His claim to fame,” Maniscalco said, “was he had the first tanning bed in the Chicagoland area.”

Maniscalco never wanted to do anything but make people laugh. His first club was the family dinner table, where he and his friends would pal around with his parents.

“Everybody loved” them, he said. “We ate together, we’re laughing together — it was almost like my parents were an extension of my friends.”

Over margherita pizza and a meatball sub at Pizzana, one of his favorite neighborhood spots in West Hollywood, a visibly tired Maniscalco itemized his manic new reality: The father of two children — both under 3 — spent all morning doing press for his current national tour, spoke to the contractor for his new, second home (formerly Gwen Stefani’s $21.6 million mansion in Beverly Hills), and was going onstage at the Comedy Store at 9:15 that night.

When he arrived, dressed in a black T-shirt and jeans, he pulled up a video he’d taken that day of his 2-year-old daughter, Serafina, getting tossed into a pool at her swimming lesson — and floating. “Do you know how to float?” he asked incredulously. “This is not how I learned to swim.”

He said he might spin that observation into a bit — generational differences are a staple in his material — and that he’s constantly noticing things that could be the seeds of something funny.

“I was doing this my whole life,” he said. “I would always come home from school and go, ‘You’re not gonna believe what happened.’”

His public debut was a book report in second grade, where he decided to do an impersonation — in costume — of his subject: Stevie Wonder. It killed.

He’s been chasing that rush ever since.

He had his cousin tape HBO stand-up specials for him and would watch them over and over. That and “Three’s Company,” starring one of his biggest influences, John Ritter.

“It’s the physicality,” he explained. “The way he would fall, or he would do something unexpectedly with his body and it just made me laugh.”

Maniscalco’s first stand-up set was in front of his fellow student body at Northern Illinois University, who “came to see the national headliner,” he said. “I won a contest to open up for him, and I got booed. The audience was primarily African American, and they were yelling ‘Sandman!’ I didn’t know what the hell Sandman was at the time, but later found out it was ‘Showtime at the Apollo’ — they call ‘Sandman’ when someone sucks. But that didn’t discourage me.”

He moved to Los Angeles in 1998 with an eye on the stage, both comedy and drama, but “my acting career sucked,” he said. So he waited tables for years at the Four Seasons in Beverly Hills while he took classes at the Comedy Store with Sandy Shore, daughter of the club’s owner, Mitzi Shore.

His comedy then wasn’t nearly as physical — and it was much angrier.

“When you start doing stand-up, you don’t feel like yourself,” he said. “I was trying to mask my low self-confidence, being onstage, with anger. It takes a while for you to find out who you are onstage.”

Open-mic nights at coffee shops eventually gave way to plum sets at established shops. He caught the attention of actor Vince Vaughn, who enlisted Maniscalco for the 2006 roadshow film, “Wild West Comedy Show: 30 Days & 30 Nights.” Variety singled him out from the three other featured comics: “Mansicalco’s pungent observations on the modern male, coupled with his fastidiousness on the road and genuine amazement at being included, flag him as pic’s most interesting and fully formed figure.”

From there he applied a work ethic, instilled in him by his father, to building a stand-up career. Salvo Maniscalco — a thrifty, exacting Sicilian who often shows up as an exaggerated character in the comic’s act — continues to hover over his son’s shoulder, figuratively and literally.

“It actually got a little tense about six, seven years ago,” Maniscalco said. “See, my father has been on my ass since I was a kid. From telling me, ‘What are you gonna do when you grow up?’ to when I played soccer — ‘Get up. You look tired. What are you doin’?’ — and then now with comedy, he’s always been like this little voice in the back of my head that I find sometimes a little annoying.”

“But oddly,” he added, “I actually feed off it. It’s almost like a coach yelling at you to get up at 5 o’clock and work out. He’s my best friend … He’s just very old-school in his approach.”

Maniscalco’s act appeals to families, often drawing on relatable issues of family dynamics, dealing with in-laws and the like. He doesn’t use his microphone to work out trauma or depression like some stand-ups, which became trickier when his parents divorced seven years ago.

“I didn’t want to talk about that at all onstage,” he said, “because it was so brutally hard for me to digest. But over the course of time, I started to see the morsels of comedy.”

He also rarely wades outside of PG-13, and hardly ever into politics. That’s partly why — in an age of provocateurs like Dave Chappelle and form-busting polemicists like Hannah Gadsby — he’s amassed a huge audience in both red and blue states.

But he’s still managed to get into hot water. At the VMAs, he poked fun at trigger warnings, participation trophies and safe spaces. Some on Twitter called him a “hack,” and in a guest column for Variety addressed to Maniscalco, safe space advocate Eleuthera Lisch wrote that she couldn’t sleep that night — that her phone blew up with “pained messages of how callous and obtuse your words felt.”

The characteristically bothered Maniscalco doesn’t seem too bothered by this.

“I didn’t come from such a coddled environment,” he said. “I was just playing on the sensitivity now of how everybody feels about what people say. I always revert back to how I was raised, and what I see today.”

When it’s mentioned that some commentators claim he plays to a “GOP consumer base,” Maniscalco laughed.

“If that falls under the ‘red states,’” he said, “it falls under the red states. I don’t know what to tell you. But it’s not politically motivated whatsoever. I didn’t come from a family of politics. I mean, we didn’t really discuss issues growing up — we discussed … recipes.”

His wife, Lana Gomez, a smiley and social artist who is his polar opposite in many ways, said Maniscalco is probably “one of the easier comedians to be married to, because he doesn’t get into a lot of controversial topics.” Still, she said, “it’s a tough time to be someone who pokes fun at everyday life, because there’s always going to be somebody who gets their feathers ruffled. No matter if you talked about, you know, a chalkboard — there’s going to be someone who gets offended.”

Maniscalco is actively investing more into acting. He’s playing Giorgio Moroder, the German composer who helped invent disco, in the upcoming film “Spinning Gold,” and is planning to shoot a movie next summer that he co-wrote. But he never wants to stop taking the mic, at the Comedy Store or across the country, and churning his botheration into laughs.

“After three, four days, if I don’t get up onstage,” he said, “I get in like a mood. I need to do it.”