The sad and painfully stinging “Anomalisa,” a beautiful big-screen whatsit, features a throng of whiners, malcontents and depressives along with one bright soul who hasn’t let disappointment break her. They’re a funny, odd group. Some register as generically prickly, full of vinegar and spit (a few may just be tired after a day’s work); others sag, as if deflating one breath at a time under an unfathomable weight. And while some carry their burden quietly and alone, others insist on sharing it, like those people who take deep, accusatory sighs when you bump into them on the subway.

This is, in other words, the human comedy as brought to you by Charlie Kaufman. He’s best known for his dense, wily, rebuslike screenplays — including “Being John Malkovich,” “Adaptation” and “Eternal Sunshine of the Spotless Mind” — and least loved for “Synecdoche, New York” (2008), the only other feature he directed before “Anomalisa.” A delirious, brutally undersung masterwork about a tormented theater director who stars in his own self-devouring production, “Synecdoche” closes with a voice providing the ultimate stage direction: “Die.” It seemed like a portentous omen given that Kaufman subsequently seemed to disappear for the next seven years.

He didn’t; he was busy working, including on the play that became “Anomalisa.” Like that production, the movie stars an excellent David Thewlis as Michael, an author and motivational speaker who has traveled to Cincinnati to deliver a speech. He meets a woman, Lisa (Jennifer Jason Leigh), and they have an intense affair. At this point it seems like a good idea to mention that all the characters in the movie are stop-motion puppets. And that all the other roles are performed by Tom Noonan, an invaluable vocalizer who creates a supporting cast of thousands (well, dozens) through a voice that rises and lowers, barks and purrs, and builds the ominous wall of sound that opens and closes the movie, as if boxing it shut.

Kaufman has a co-director this time out, Duke Johnson, who’s a partner in the production company that turned the play into an animation. They make a seamless team. “Anomalisa” is a recognizably Kaufmanesque creation in its anarchic and mordant humor, its singular narrative beats and especially in its preoccupations (identity, authenticity, loneliness, death, love, pleasure, the usual). And this isn’t the first time that Kaufman’s work has involved puppets. The lead character in “Being John Malkovich,” directed by Spike Jonze, is an unhappy puppeteer who works with marionettes that look like him and his wife. In a surreal turn, the puppeteer finds a portal into the mind of the title character (played by Malkovich), who becomes something of a puppet pulling strings of his own.

It’s complicated, as are most of Kaufman’s scripts, but “Anomalisa” is more narratively and philosophically streamlined. It also clocks in at a well-timed 90 minutes, a relatively abbreviated length that fits this hermetically sealed, precariously unoxygenated world, with its doll-size scale, human avatars, fabricated environments and locked-down protagonist. The filmmakers delay Michael’s introduction, opening with a babble that rises against a black screen: Enter, the great abyss! Next up is a pale cloudy sky — it’s the most expansive image in the movie as well as the only representation of the natural world — a dreamscape that’s soon pierced by the plane taking Michael to his talk in Cincinnati.

With his sallow complexion, drooping eyes and air of exhaustion (or perhaps exasperation), Michael could be merely another business traveler. Well, except that he’s a puppet, one with strange black seams that run along his hairline, down his chin and cut temple to temple, dissecting his face into discrete quadrants. He’s also a puppet that is shortly popping a prescription pill, a moment that — with his melancholic resignation, the usual nightmare of plane travel, the droningly familiar voices that swell around him — rapidly makes Michael feel somewhat real, more recognizable than not. That’s because while “Anomalisa” is filled with uncomfortably, at times sourly humorous moments, it’s also a horror movie about the agonizing, banal surrealism of everyday life.

Kaufman’s gift for quotidian horror remains startling; he’s a whiz at minor miseries. The story progresses through a series of squirmy encounters with other characters who, despite variations in clothing and hair, all have the same eerily blank faces. Once Michael breaks free of the airport herd, most of these faces are attached to service workers of one type or another who, with degrees of friendliness and hostility masquerading as affability (or professionalism), roll out like dolls on an assembly line. One after another, with voices that Noonan distinguishes with modulations in pitch and an occasional curse, they serve Michael: the asthmatic cabdriver; the obsequious hotel clerk and bellhop; the room-service worker; the grumpy waitress.

Lisa turns out to be the exception to this manufactured nightmare (she’s the anomaly of the title), and Michael falls hard. “Your voice!” he cries out in wonder, a moment of lyricism that the filmmakers tuck in between unbuttoned clothes and an admirably uncomfortable, honest sex scene. Lisa may seem like a mess — she voluntarily enumerates her supposed failings, like someone who’s memorized other people’s criticisms of her — yet she’s glorious. And Leigh, who brings Lisa to trembling life with soft mewls of feeling, perfectly timed pauses and a poignant a cappella rendition of “Girls Just Want to Have Fun,” makes you see how much is at stake both for her and Michael. Whether he can hear her is one heart-skipping-ly moving question; whether he deserves to is another.

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“Anomalisa” is an Oscar nominee for Animated Feature Film.