Lowe, who recently starred in HBO's "Behind the Candelabra" as Liberace's plastic surgeon Dr Startz, is tapped to portray President John F Kennedy in National Geographic Channel's movie "Killing Kennedy".
He will be paired with "Once Upon a Time" actress Goodwin who is cast as First Lady Jacqueline Kennedy.
"Buffy the Vampire Slayer" alumna Michelle Trachtenberg was earlier picked to play Lee Harvey Oswald's wife Marina.
"We are thrilled to be working with Rob Lowe, Ginnifer Goodwin and Michelle Trachtenberg, three gifted artists who have responded to this timely, authentic and entertaining material," Howard T Owens, president of the National Geographic Channels, said in a statement.
The two-hour drama is adapted from Bill O'Reilly's 'Killing Kennedy: The End of Camelot'.
"Killing Kennedy" chronicles the final years of Kennedy and his assassin Oswald, who is yet to be cast.
