Santana signed with the Anaheim Angels as an amateur free agent on September 2, 2000. He was a starting pitcher for the Angels' Double-A affiliate, the Arkansas Travelers early in 2005, where he posted a 5–1 record and 2.31 ERA in 7 starts. Following an injury to Angels starting pitcher Kelvim Escobar, Santana earned a promotion. He made his first major league appearance on May 17, 2005, against the Cleveland Indians, in which he gave up the pitching version of the cycle in first four batters that he faced. In his second start, facing the Chicago White Sox's Jon Garland, (who at the time had the best record in baseball), Santana bested Garland by pitching a complete game shutout. He gave up only 5 hits and struck out 7 for his first career victory. Santana then went on the disabled list and was sent back down to the minors to the Angels' Triple-A affiliate, the Salt Lake Bees.