The Ellen DeGeneres Show host will be honoured for her contributions to comedy by the John F Kennedy Centre for the Performing Arts in Washington DC this fall.
Will Ferrell received the Mark Twain Prize in 2011, with other previous winners including Tina Fey, George Carlin and Whoopi Goldberg.
DeGeneres said of receiving the prestigious award: "To get the same award that has been given to people like Bill Cosby, Tina Fey and Will Ferrell, it really makes me wonder... why didn't I get this sooner?"
The ceremony will be taped on October 22 and will air at a later date on US television.
Tickets for the 2012 Mark Twain Prize Prize ceremony go on sale on August 8.
Watch a clip from Tina Fey's Mark Twain Prize gala below: