The 85-year-old comedian and Las Vegas resident issued a statement Monday through the Tucson, Ariz.-based Muscular Dystrophy Association calling it time for a "new telethon era."
He says he'll make his final appearance on the six-hour primetime telethon Sept. 4 by performing his song "You'll Never Walk Alone."
Lewis says he'll continue as the association's national chairman, a role he's held since the early 1950s.
Lewis' first Labor Day weekend telethon in 1966 was broadcast by a single New York City television station and raised more than $1 million.
Last year's Jerry Lewis MDA Telethon raised almost $59 million to fund research to find a cure for muscular dystrophy and ALS, or Lou Gehrig's disease.