In 2013, Santiago split between the White Sox bullpen and the rotation, finishing with 23 starts while also appearing 11 times out of the bullpen. Although his ERA for the season was 3.56, his record was just 4-9 for the White Sox.
Santiago was traded to the Los Angeles Angels of Anaheim on December 10, 2013, in a three-team trade involving the Chicago White Sox, the Arizona Diamondbacks, and the Los Angeles Angels. The Angels received Tyler Skaggs along with Santiago, while the White Sox received Adam Eaton and the Diamondbacks received Mark Trumbo and two players to be named later. In his first season in Anaheim, Santiago was fairly inconsistent, he averaged less than 6 innings per start and for a moment was sent to the bullpen, where he made 6 appearances while also starting 24 times for the Angels. In 127.1 innings, Santiago went 6-9 with a 3.75 ERA.