The actress, best known for her roles on Seinfeld, The New Adventures of Old Christine and Veep, will receive the award on October 21 during an event at the Kennedy Center Concert Hall in Washington, D.C.
The Mark Twain Prize for American Humor recognizes those who have had an impact on American society in similar ways as Twain, a novelist.
"Merely to join the list of distinguished recipients of this award would be honor enough, but, as a student of both American history and literature, the fact that Mr. Twain himself will be presenting the award to me in person is particularly gratifying," Louis-Dreyfus said in a statement.
"Like Mark Twain, Julia has enriched American culture with her iconic, unforgettable and outright hilarious brand of humor," said Kennedy Center president Deborah F. Rutter. "Over four decades, her wildly original characters and her gift for physical comedy have left us in stitches. Julia is a role model for so many, and we look forward to honoring her on October 21."
Louis-Dreyfus, who has been battling breast cancer, is expected to return to work on HBO's Veep in August with the seventh and final season of the comedy airing in 2019.