The Emmy Award-winning comedienne was feted in a ceremony at the Kennedy Center for the Performing Arts in Washington, D.C., and the audience was packed with colleagues from her former show Saturday Night Live and current TV project 30 Rock.
Fey's movie co-star Carell took to the stage to present his pal with the prize, describing her as "a pretty cool cucumber" and adding, "She dares to offend and shrugs off the obvious choice. She has the uncanny ability to make something out of nothing."
The 40-year-old funnywoman, who is the youngest ever recipient of the award, thanked her pals for turning out for the ceremony, adding, "It means so much to me that you care about showbiz more than your families."
Also in the audience were 30 Rock's Alec Baldwin and Tracy Morgan, Steve Martin, Jon Hamm, Amy Poehler, Jimmy Fallon, Jane Krakowski, Jennifer Hudson and Betty White.
Fey is the third woman to receive the Mark Twain prize after Lily Tomlin and Whoopi Goldberg.