The Duplass brothers, Jay and Mark, helped establish the mumblecore sub-genre of independent film with “The Puffy Chair,” a low-key comedy that amused Sundance audiences in 2005. Their next joint effort, “Baghead,” cleverly satirized the very genre it was part of, demonstrating great self-awareness on the Duplasses’ part. Their third feature, “Cyrus,” shows even more growth, a warm, hilarious story that’s as smartly executed as anything I’ve seen in a while.

At first glance, you might think the Duplass boys had gone Hollywood. Instead of casting themselves or their indie friends as actors, they got bona fide celebrities: John C. Reilly, Marisa Tomei, Jonah Hill, Catherine Keener. Another pair of director brothers, Ridley and Tony Scott, served as producers. Gone are the charmingly low-budget production values and the handheld cameras.

But do not fear! The Duplasses have adapted extremely well, their sensibilities intact despite the Hollywood influences. “Cyrus” takes a broad comedic premise, gets laughs out of it, then somehow manages to treat it realistically, too. What could have been a silly farce is instead a down-to-earth, highly enjoyable film.

Reilly plays a fellow named John, a Los Angeles schlub who is, by all the usual standards, a loser — but since he’s played by Reilly, we like him anyway. (Is anyone better at being pathetic and lovable at the same time?) John has been divorced from Jamie (Keener) for seven years but has failed to get over her, and is now thrown into a more dramatic tailspin at the news she’s remarrying. At her insistence that he get out and meet some new people, he goes to a party, where he gets absurdly drunk and provides us with some almost unbearably awkward comedy. Then he meets a woman named Molly (Tomei), who stumbles across him while he’s in the back yard, peeing in the bushes.

Molly, who is beautiful and mature, is smitten with John, who is astonished and compares himself to Shrek. The beginnings of a relationship develop, hindered by one thing: Molly’s 21-year-old son, Cyrus (Hill), who lives with her, spends every waking hour with her, and is more than a little weird.

The rivalry between Cyrus and John provides plenty of great laughs. Hill and Reilly are old pros at this sort of thing, and they’re clearly comfortable with the Duplass brothers’ loose style of comedy. But at every turn, just when you think the film will become a generic son-doesn’t-like-the-new-boyfriend caper — or a dark comedy about a too-close mother and son — the Duplasses reign it in. Cyrus’ behavior is loony at first, like a satisfying but not very deep “SNL” character, and then he evolves into a more realistic, believable figure. Likewise, John, a one-dimensional loser in the beginning, becomes a real person, and the dynamic between him, Cyrus, and Molly starts to feel relatable.

It would have been easy for the filmmakers to go just for the laughs and leave the sentiment out of it. There’s nothing wrong with a movie like that, but adding some depth and nuance can make it a richer experience. Here the Duplass brothers have shown they can make a “mainstream” movie, with recognizable actors and a respectable budget, without forsaking the humanity and wit that make their work so distinct.

A- (1 hr., 30 min.; R, a dozen or so F-words, brief partial nudity, a little sexuality.)