Holmes will executive produce and direct one of the episodes of the four-hour series.
The first "Kennedys" miniseries was originally intended to air on The History Channel, but it was dropped due to controversy about how it depicted the political family.
Holmes was last seen on Broadway in Theresa Rebeck's Dead Accounts. Her stage credits also include All My Sons, and she starred on the TV show "Dawson's Creek." Her film work includes "Thank You for Smoking," "Batman Begins" and "Pieces of April."
"'The Kennedys' was a brilliant execution of storytelling based on the lives of one of the world’s best known families," Reelz CEO Stan E. Hubbard told Variety. "We are delighted that we were able to step up and acquire the broadcast rights to that property and we have every confidence that this new miniseries will be as enthusiastically received as the last one."