Killing Kennedy is an adaptation of the non-fiction book about President John F Kennedy's assassination by Bill O'Reilly.
Lowe will portray President Kennedy, while Once Upon a Time star Goodwin will play first lady Jacqueline Kennedy, states The Hollywood Reporter.
Michelle Trachtenberg will appear in a Russian-speaking role as Marina Oswald, the wife of alleged assassin Lee Harvey Oswald.
"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," said Howard T Owens, president of the National Geographic Channels.
"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."
O'Reilly's Killing Lincoln was previously adapted for the channel three months ago, grabbing 3.4 million viewers.
Production for the new project begins in June in Richmond, Virginia.