In 1999, Palladino landed his breakthrough starring role, one month after returning from the U-571 shoot in Rome, on ER as Dr. Dave Malucci, which he played in the sixth season until the eighth season in 2001. In 2005, he starred in the critically acclaimed FX war drama Over There as Sgt. Scream, the leader of a squad of U.S. 3rd Infantry Division Soldiers involved in the 2003 Invasion of Iraq.