O'Donnell, who grew up in Commack on Long Island, got her start as a stand-up comedienne performing in clubs in the New York area.
She will both host and do stand-up at the festival's opening night on Tuesday, Nov. 6 at 8 p.m. at Avery Fisher Hall at Lincoln Center.
"I am honored to open this year's New York Comedy Festival! There is no better city in the world and I am looking forward to taking the stage for a great cause," O'Donnell said in a statement.
The Fourth Annual NYCF's roster also includes celebrated comics Sarah Silverman performing at Carnegie Hall on Nov. 7; Denis Leary at the Beacon Theatre on Nov. 8; Louis CK at Town Hall on Nov. 8; Artie Lange at Town Hall on Nov. 9; Damon Wayans at the Beacon Theatre on Nov. 9; Bill Maher at the Beacon Theatre on Nov. 10 and Seth MacFarlane at Avery Fisher Hall on Nov. 11.