The 24-year-old right-hander was optioned by the Angels to Triple-A Salt Lake prior to Wednesday's game in order to make room for catcher Mike Napoli, who was activated from the disabled list.
Santana, a 16-game winner last season, is 5-11 with a 6.22 ERA in 19 starts so far this season. He had struggled mightily lately, dropping his last four starts and compiling an 11.64 ERA during that time.
The news followed Santana's most recent disappointment on Tuesday, when he allowed 14 hits and seven earned runs in a loss to Tampa Bay. The 14 hits were the most allowed by an Angels pitcher this season, and just one shy of the club record set in 1976 by Paul Hartzell.
Napoli has been disabled since he sustained a high left ankle sprain in a home plate collision July 1 at Baltimore. He was hitting .243 (43-for-177) with eight homers and 29 RBIs at the time of the injury, which led to the first time the 25-year-old had been on the DL in his two-year career.