FilmNation CEO Glen Basner said, "It simply doesn't get much better than this, especially for us New Yorkers" in confirming Penn's role behind the camera.
"The Comedian" will star De Niro as an over-the-hill comic sentenced to community service after assaulting an audience member. He meets up with Kristin Wiig while paying his debt to society.
The film will be the seventh Penn has directed and first since 2007's "Into the Wild."
Britain's The Guardian said "The Comedian" is part of a full plate for De Niro. The 68-year-old actor has six movies scheduled for release next year.