Celebrated director Anna D. Shapiro pulls no punches in her savage take on “Of Mice and Men,” the American lit classic about migrant farmhands in Depression-era California, now open at the Longacre Theatre. It certainly helps that she has two gifted performers as her leading men, James Franco and Chris O’Dowd, both making memorable debuts.

As matters get underway, George Milton (Franco) and Lennie Small (O’Dowd) are quarreling over the dead mouse Lennie has in his pocket. It’s soft, and it’s Lennie’s pet, and we see the sadness in O’Dowd’s eyes when Franco hurls the creature into a river.

That moment sends a clear signal: the prevalent theme in this staging is our need for companionship. We see it in the way a farmhand’s wife (Leighton Meester, of TV’s “Gossip Girl”) seeks attention in a room of rambunctious men, and in the symbiotic relationship between George and Lennie. But it’s most evident in the ways animals are worked into this production, the play’s first Broadway revival in four decades.

Witness the stillness that descends upon the audience when Carlson, a determined fieldworker (Joel Marsh Garland), separates the old one-armed farmhand (Jim Norton, a Tony-winner for “The Seafarer”) from his precious mutt, who “stinks like hell.” A good 30 seconds or so—it feels like forever—elapses between the time Carlson walks the dog outside, and the gunshot we know is coming. The moment here is played for all the tension Shapiro can wring out of it, and it foreshadows things to come for George, a savvy man of the world, and Lennie, a gentle giant with no sense of his strength.

It’s O’Dowd (the doughy Irish actor and comic, of “Bridesmaids”), as Lennie, who has the hardest job. We need only to see the easygoing way he cradles a newborn puppy to understand his characterization. His Lennie is a human being of emotional intelligence, whose overwhelming feelings often get the better of him. O’Dowd gives an endearing interpretation of a mentally addled man who wants nothing more than “to live off the fat of the land.”

Franco, the performer-director-writer-teacher—geez, he’s such a multitasker that he even appears in a Gucci ad on the back of the Playbill—is such a cult object that I feared his presence would throw the characters out of equilibrium. My fears were unwarranted, because he gives such an understated and natural performance.

Case in point, the way Franco’s George reacts when Lennie gets worked up about the still-imaginary rabbits they would one day have on their farm. Instead of calming his hysterical friend, Franco leans back on his chair and makes a noise, an imitation of a screeching cat. This George respects Lennie enough to engage in that most intimate of friendship rituals: teasing.

Meester also makes her Broadway debut, as “Curley’s wife,” a character so devoid of identity that she doesn’t warrant a first name. Dressed like a 1930s starlet, she is merely flirty when she pops in to the workers’ bunkhouse, “jus lookin’ for somebody to talk to.” But she reveals a sweetness and openness in the second act, sitting with Lennie in the barn, as she invites him to touch her hair.

A half-dozen supporting players are all distinguished, in particular Jim Parrack, as Slim, the even-keeled “jerkline skinner,” who understands the relationship between George and Lennie, and Ron Cephas Jones as Crooks, a black stablehand segregated from his coworkers, whose appearance in the first scene illustrates that financial woes weren’t the only themes Steinbeck explored in his 1937 work (the play was written alongside the novella).

The story’s two climactic gunshots—one at the end of each act—are so well-known that they’re in danger of being anticlimactic, but Shapiro knows how to draw out tension and play on the chemistry her characters have established to make them both utterly chilling. (Fans of “The Walking Dead” will discover a fascinating parallel here.) I left the theater desperately wishing things hadn’t gone as awry as they did.

“Of Mice and Men,” through July 27 at the Longacre Theatre, 220 W. 48th St. Tickets: $42-$135. Call Telecharge, 212-239-6200.

Follow Robert Kahn on Twitter@RobertKahn