The 46-year-old actor will play Ted Kennedy on the series, which is set to telecast on Reelz channel, reported Variety.
Perry will also serve as an executive producer on the four-part miniseries. Holmes is reprising her role as Jackie Kennedy Onassis.
The project is set to debut in 2017.
Perry will portray 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.
"We are privileged to have an actor of Matthew Perry's stature and ability take on the role of such a complex and controversial figure as Ted Kennedy," said executive producer Michael Prupas, president of Muse Entertainment, which is producing the project.
"Matthew Perry and Katie Holmes will fascinate audiences around the world as they bring these two famous Americans to life.
