The CNN programme will be holding its Guest Host Week with the former ABC talk show presenter kicking off the special week on Tuesday, May 29.
Executive producer Jonathan Wald posted on his Twitter: "You guys: Regis Philbin returns to TV for one night, filling in for @piersmorgan Tuesday. His guest, David Letterman. Must see next week."
Philbin stepped down from his co-hosting duties on ABC's Live with Regis and Kelly in November 2011.
Kelly Ripa continued to host her own daytime talk show called Live! with Kelly with a series of guest presenters.
However, New York Giants player Michael Strahan is said to be the favourite to appear alongside Ripa as her permanent co-host.
Piers Morgan Tonight airs weeknights at 9pm ET on CNN.
Watch a clip of Piers Morgan Tonight below: