The television personality has presented the annual fundraiser since 1966 but announced this week that the upcoming 2011 telethon will mark his last appearance as host.
In a statement posted on the organisation's official website, he said that he would bow out with a rendition of his "signature song" 'You'll Never Walk Alone'.
"It's time for an all new telethon era," he said, promising that this year's six-hour special on September 4 will be "spectacular".
"We're so close to treatments that it's absolutely vital for everyone to tune in and make a generous donation," he said. "America has always found a way each year to give me that just one dollar more to help my kids.
"I'll continue to serve MDA as its National Chairman - as I've done since the early 1950s. I'll never desert MDA and my kids."
MDA President & CEO Gerald C. Weinberg paid tribute to Lewis's work with the telethon, praising him for inspiring his co-workers and people across the world.
"We're deeply honoured that Jerry Lewis will continue as MDA's National Chairman and we're profoundly grateful for everything he has done and is doing for the Association," he said.
Last year's telethon raised more than $58 million and was watched by around 40 million people.