Production on the cable television film is to begin next month in the Richmond, Va., area. It will premiere later this year to mark the 50th anniversary of Kennedy's assassination.
The film is based on the best-selling book by Bill O'Reilly and Martin Dugard.
"We are thrilled to be working with Rob Lowe, Ginnifer Goodwin and Michelle Trachtenberg, three gifted artists whom have responded to this timely, authentic and entertaining material," Howard T. Owens, president of the National Geographic Channels, said in a statement Tuesday.
"With 'Killing Kennedy,' timed to coincide with the 50th anniversary of the assassination of JFK, National Geographic Channel continues to bring daring, culturally significant television events to our growing global audience."
Lowe is best known for his work on the TV political drama series "The West Wing." He can be seen in the sitcom "Parks and Recreation" and in the TV movie "Behind the Candelabra."