The 31-year-old right-hander agreed to a $14.1 million, one-year contract on March 12. He started for Triple-A Gwinnett on Friday and allowed six runs - five earned - and eight hits in 5 1-3 innings during a 12-7 win over Durham.
He faces Zack Wheeler in the middle game of the three-game series.
Atlanta opened with a four-man rotation while waiting for Santana, left-hander Mike Minor and right-hander Gavin Floyd to join the pitching staff. Minor's spring training was slowed by tendinitis in his left shoulder, and Floyd is returning from elbow surgery last May 7.
Minor and Floyd were to pitch for Gwinnett at Norfolk on Tuesday night.