The award has been presented since 1998 as a way to recognise those who have made significant contributions to humour and commentary in the United States.
Previous winners include Conan O'Brien, Dave Chappelle, Julia Louis-Dreyfus, David Letterman, Carol Burnett and Tina Fey.
Speaking ahead of Sunday's ceremony, Maher called the prize a great honour.
"Who doesn't like awards and wouldn't want to be compared to Mark Twain, especially for what I do?" he said.
"And, you know, they've had a lot of amazing winners who I'm huge fans of. Not all of them are anything like Mark Twain. I am at least somewhat like Mark Twain. ... He took on both sides."
President Donald Trump, who has spent much of his second term reshaping the performing arts venue, didn't attend.
The future of the Kennedy Center hung over the event.
Shortly after Trump returned to the White House in January 2025, the Republican president fired much of the centre's leadership and installed a board largely composed of allies.
It named Trump as chairman and his name was added to the building's iconic facade, prompting a legal battle that became a proxy fight over the extent of the president's power.
Trump later said the Kennedy Center would close in July for a two-year renovation.
But District Judge Christopher Cooper upended those plans in May by ruling that Trump's name was illegally added to the building, ordering it removed. The judge also has blocked the closure.
