The channel announced Wednesday that Kinnear will play President John F. Kennedy, and Holmes will portray first lady Jacqueline Kennedy in the eight-hour program about the famous family.
Barry Pepper is set to play Robert Kennedy, who served as U.S. attorney general in his brother's administration. Tom Wilkinson is cast as patriarch Joseph Kennedy.
Joel Surnow, creator of "24," is set to produce the series, which will focus on the early years of JFK's presidency before he was assassinated in 1963, the New York Post reports.
Kinnear has starred in "Flash of Genius, "Baby Mama," "Little Miss Sunshine" and more recently "The Last Song" with Miley Cyrus.
Holmes, one of the stars of TV's "Dawson's Creek," has appeared in such movie sas "Batman Begins" and "Thank You For Not Smoking." She made her Broadway debut in the revival of Arthur Miller's "All My Sons" in 2008.
The Kennedy's personal drama will be part of the saga along with major events of their time, the channel has said.
The miniseries is scheduled to air on the History Channel in 2011.