Perry will also serve as an executive producer on the program, which is the adaptation of the book After Camelot: A Personal History of the Kennedy Family 1968 to the Present by J. Randy Taraborrelli.
The follow-up to 2011's The Kennedys is expected to premiere in spring 2017.
"Matthew Perry portrays Ted Kennedy in the years following the assassinations of his brothers Jack and Bobby and depicts his very complicated public and private life as he tries to live up to the Kennedy family political ambition and fill a male leadership void in the family itself," the cable network said on its website. "Perry joins Katie Holmes, portraying Jackie Kennedy Onassis, who despite her desire for privacy had arguably become the most famous and admired woman in the world. Jackie's ties to the Kennedy family remained strong throughout her life and her relationship with her brother-in-law Ted grew ever closer as they constantly turned to one another for support and as confidantes."