The 85-year-old's name has become synonymous with the telethon, which he has hosted since 1966. Lewis issued a statement through the association calling it "time for an all new Telethon era."
"I'll be making my final appearance on the show this year by performing my signature song, `You'll Never Walk Alone,"' Lewis said of a shortened six-hour primetime broadcast scheduled for Sept. 4.
Lewis, a Las Vegas resident, has in recent years battled a debilitating back condition, heart issues and the crippling lung disease pulmonary fibrosis. He said he'll continue serving as national Muscular Dystrophy Association chairman, as he's done since the early 1950s.
A spokesperson for MDA says more than $1 billion has been raised during telethons over the years.
The Associated Press contributed to this report.