The 54-year-old said he was "deeply honoured... to join the distinguished list of past recipients of this award."
First presented to Richard Pryor in 1998, the award is named after the 19th Century novelist and essayist who was born Samuel Clemens in 1835.
It is given annually to someone who has had an impact on US society through their humour and social commentary.
Other previous recipients include Bill Cosby, Ellen DeGeneres and talk show host Jay Leno, last year's honouree.
Born in Brooklyn in 1961, Murphy got his break in comedy in 1980 when he joined the cast of Saturday Night Live.
He went on to become one of the movie industry's top box-office performers thanks to such hits as Beverly Hills Cop, Coming to America and the animated Shrek films.
Murphy will be presented with the prize at a ceremony on 18 October at the John F Kennedy Center for the Performing Arts in Washington, DC.
Actor and comedian Eddie Murphy is to receive this year's Mark Twain Prize for American humour.