Having first come to prominence for writing Being John Malkovich (1999), Adaptation (2002), and Eternal Sunshine of the Spotless Mind (2004), he went on to direct films based on his own screenplays: Synecdoche, New York (2008), Anomalisa (2015), and I'm Thinking of Ending Things (2020).

[14] In hope of finding a talent agent, he wrote a portfolio of spec scripts based on television series such as Married... with Children, Newhart, It's Garry Shandling's Show and The Simpsons.

The only offer he got was a Comedy Central series titled Access America, hosted by actor Fred Willard, which coincidentally was being filmed in Minneapolis.

He continued to work on other comedic series: Fox's sketch comedy show The Edge, The Trouble with Larry and Ned and Stacey, the last of which he also produced.

The most notable series he worked on in this period was The Dana Carvey Show, which featured writers and performers such as Louis C.K., Robert Smigel, Greg Daniels, Stephen Colbert and Steve Carell.

These unproduced projects included a script for an adaptation of Philip K. Dick's novel A Scanner Darkly, a pitch for a star vehicle for Don Rickles and Rodney Dangerfield in which they would play a washed-up, murderous comedy duo (an idea Kaufman used in Antkind), and a pitch for a R-rated version of the TV series Gilligan's Island.

Kaufman first came to mainstream notice as the writer of Being John Malkovich, directed by Spike Jonze, earning an Academy Award nomination for his effort and winning a BAFTA.

Kaufman won his first Academy Award for Best Original Screenplay and third BAFTA for the film together with Gondry and French artist Pierre Bismuth.

[20] David Edelstein described the film in Slate as "The Awful Truth turned inside-out by Philip K. Dick, with nods to Samuel Beckett, Chris Marker, John Guare—the greatest dramatists of our modern fractured consciousness.

[23] Due to scheduling conflicts, later productions of Theater of the New Ear did not feature the Coens' play, replacing it with Anomalisa, which Kaufman wrote under the pseudonym "'Francis Fregoli".

Anomalisa centers on a man (David Thewlis) who perceives everyone in the world to be the same person (Tom Noonan) until he meets an exception (Jennifer Jason Leigh).

[29][30] The film's poor box office resulted in Kaufman finding it difficult to gain funding for scripts to which he has attached himself as director.

Few details have been confirmed about the plot, except that it is a musical comedy about internet anger culture and was set to star Jack Black, Nicolas Cage, Steve Carell, Kevin Kline, Catherine Keener, Paul Reubens, Jacki Weaver and Elizabeth Banks.

[32] In July 2012, Black said that funding for the project had fallen through, as the studio was unsure about its chances for success after the financial failure of Synecdoche, New York.

[35] In April 2012, Kaufman was hired to adapt Patrick Ness's Chaos Walking book series, of which he wrote the first draft before leaving the project.

[40] Kaufman co-directed the film with Duke Johnson, who had previous experience in stop motion filmmaking, and the original cast of the play production returned to reprise their roles.

"[47][48] The project began filming in March 2019, with Jessie Buckley having replaced Larson, and Toni Collette and David Thewlis joining the cast, and was released on Netflix in September 2020 to positive reviews.

Based on a poem by Eva H.D., who also portrays the lead character, the film was shot entirely on a Samsung Galaxy S22 smartphone by cinematographer Chayse Irvin.

[52] Kaufman's works explore such universal themes as identity crisis, mortality, and the meaning of life through a metaphysical or parapsychological framework.

[53] He uses metafiction as a literary device, and sometimes includes fictionalized "facts" about his life in his work, notably Adaptation., Hope Leaves the Theater, and Antkind.

[54] Non-human primates also recur in Kaufman's early work: in Being John Malkovich, Lotte has a pet chimpanzee named Elijah; in Human Nature, Puff was raised as a chimpanzee; in Confessions of a Dangerous Mind, Penny dreams about a monkey; and in Adaptation, the original deus ex machina was a Bigfoot-like "Swamp Ape".

[55] Some writers and directors Kaufman has named as favorites of his, or as influences, are Franz Kafka,[33] Samuel Beckett,[56] Eugene Ionesco, Stanisław Lem,[57] Flannery O'Connor,[58] Shirley Jackson,[58] Philip K. Dick,[59] Patricia Highsmith,[59] Stephen Dixon,[59] David Lynch,[33] Lars von Trier,[33] Roy Andersson,[33] Woody Allen,[60] and the Coen brothers.