Antonelli was called up to the Padres on September 1, 2008, where he promptly laced a single off Greg Maddux of the Dodgers for his first hit in the major leagues. He then went hitless in his next 20 at bats, but then got 7 hits in his next 13 at-bats with 3 walks, including his first home run, on September 15, off of Colorado Rockies pitcher Jason Hirsh. He was unable to earn another big league promotion with the club, and he was granted free agency at the end of the 2010 season.