The veteran Raging Bull actor had previously been rumoured in connection to a role in the Michael Douglas-led ensemble comedy.
De Niro will play party averse Paddy Connelly, who reluctantly joins his friends in on the trip to Las Vegas, according to The Hollywood Reporter.
Based on a screenplay by Dan Fogelman, the movie follows four ageing friends who gather for a bachelor party in the Nevada city, where Douglas and De Niro's characters vie for the attention of an attractive lounge singer.
Dustin Hoffman and Christopher Walken have been linked to the roles of the other two companions, but scheduling clashes make their involvement look unlikely at this time.
National Treasure director Jon Turteltaub is slated to helm the movie for CBS Films from a script written by Dan Fogelman (Crazy, Stupid, Love).
Last Vegas is scheduled to begin shooting in Atlanta this August.