Bill Hader and Jane Lynch have also signed up for roles in the movie, which is to be directed by Greg Mottola. Mottola's film credits include "Superbad" and "Adventureland."
Rogen, who had a supporting role in "Superbad," will play the title character's voice in "Paul."
Pegg and Frost, who previously collaborated on "Shaun of the Dead" and "Hot Fuzz," co-wrote the screenplay for "Paul" and will serve as the film's leads.
"In the comedy adventure, Pegg and Frost play two sci-fi fanatics on a road trip whose conspiracy dreams come true when they encounter an escaped alien near Area 51," the companies said in a news release. "As they try to reunite him with his mother ship, they find Paul has many more opinions than your typical E.T."
The film is set to begin principal photography next month.