MDA announced earlier this month that longtime host Jerry Lewis had completed his run as the charity's honorary chairman and would not be appearing on the annual telethon for the first time in more than 40 years.
The charity organisation has now confirmed that Lythgoe, Sweeney, Entertainment Tonight's Nancy O'Dell and journalist Jann Carl will replace Lewis as co-hosts for the Labour Day weekend telecast.
Celine Dion, Lady Antebellum, Martina McBride and Jordin Sparks have been lined-up as musical guests, while American Idol judges Jennifer Lopez, Steven Tyler and Randy Jackson and the cast of The View will also make special appearances.
Telethon producer Lee Miller touted the show's all-star line-up, saying: "Songs and appeals by these outstanding artists, as well as extraordinary Penn & Teller magic and so much more, undoubtedly will captivate tens of millions of viewers.
"Then, when America sees and hears from remarkable families served by MDA, people once again will find it near impossible to not respond generously."
This year's MDA telethon will air over a six-hour stretch of primetime on Sunday, September 4, marking a change from the usual 21-hour format.
Earlier this month, comedians Larry Miller and Paul Rodriguez protested Lewis's MDA departure at the Laugh Factory comedy club in Hollywood.
> Jerry Lewis: American Idol contestants are McDonald's wipeouts'
Watch Celine Dion perform 'My Love' on the 2008 MDA Telethon below: