The awards will take place on Sunday evening local time.
O'Brien, 61, was named the latest recipient of the award for lifetime achievement in comedy in mid-January, about three weeks before President Donald Trump upended the Kennedy Center by ousting the longtime president and the board chairman. Trump dismissed the board of directors and replaced them with loyalists, who then elected him as chairman.
In announcing the changes, Trump posted on social media that the dismissed individuals "do not share our Vision for a Golden Age in Arts and Culture."
How that vision takes shape remains to be seen, but Trump has spoken about wanting to book more Broadway shows there and floated the idea of granting Kennedy Center Honors status to actor Sylvester Stallone and singer-songwriter Paul Anka.
Into this maelstrom steps O'Brien, whose comedic persona has never been particularly political. The comic has always tended more towards goofiness and self-deprecation. But he has also leaned into sensitive societal issues at times, officiating his longtime costume designer's gay wedding live on his show in 2011.
O'Brien vaulted into the spotlight from near-total obscurity in 1993 when he was chosen to replace David Letterman as host of Late Night despite no significant on-camera experience.
The former Harvard Lampoon editor had spent the previous years as a writer for Saturday Night Live and The Simpsons, appearing on camera only as an occasional background extra in SNL skits.
He went on to host Late Night for 16 years, longer than any other host. O'Brien was later tapped to replace Jay Leno as host of The Tonight Show, but that experiment ended in public failure.
O'Brien went on to host another talk show on the cable station TBS, while launching successful podcasts and travel shows. His recent gig hosting the Academy Awards was so well received that the producers announced they are bringing him back next year.
In the wake of Trump's takeover of the Kennedy Center, several artists, including the producers of Hamilton and actress and writer Issa Rae, announced they were canceling appearances at the venue.
Others have chosen to perform while making their sentiments known from the stage. Leftist comic W Kamau Bell directly addressed the controversy in his performance just days after the shake-up. Earlier this month, cellist Erin Murphy ended her set with a performance of the Woody Guthrie protest anthem, All You Fascists Bound to Lose.
Mark Twain recipients typically receive tributes and testimonials from a star-studded collection of comics and celebrities. Given the nature of comedians, it seems likely that some of them on Sunday evening will address the issue of the institution's uncertain future.
Other comedians receiving the lifetime achievement award include both Letterman and Leno, along with George Carlin, Whoopi Goldberg, Bob Newhart, Carol Burnett Bill Murray and Dave Chappelle.
