Santana was hit on the backside by a line drive, and he felt pain in his Achilles while chasing the ball.
Santana, on the 15-day disabled list while recovering from shoulder surgery, likely was making his last start in extended spring training before joining an affiliate.
Kevin Gausman will be officially recalled on Saturday and start against the Athletics at Camden Yards. He will oppose another former first-round pick, right-hander Sonny Gray.
This will be Gausman's second start with the Orioles in 2014 after allowing five runs and six hits in four innings against the Tigers on May 14. He's currently on the taxi squad.
Gausman is starting in place of right-hander Miguel Gonzalez, who went on the 15-day disabled list retroactive to May 31 with a strained right oblique.
Gonzalez will pitch next week at Double-A Bowie or Single-A Frederick on his injury rehab assignment. His next start with the Orioles is expected to fall between June 15-17.
The Orioles also optioned reliever Preston Guilmet, who's been scored upon in his last four appearances. They recalled left-hander Tim Berry from Double-A Bowie and purchased the contract of reliever Evan Meek.
Rule 5 pick Michael Almanzar was transferred to the 60-day disabled list to make room for Meek on the 40-man roster.
Berry, the 50th-round pick in the 2009 First-Year Player Draft, is expected to be optioned to Bowie on Saturday to make room for Gausman on the 25-man roster.
Reliever Tommy Hunter still is scheduled to pitch Saturday night at Single-A Delmarva. Assuming there are no setbacks with his groin injury, Hunter will be activated by the Orioles on Sunday.
Hunter wasn't a consideration for the bullpen tonight because he pitched two innings yesterday in a simulated game yesterday in Arlington, Texas. The Orioles wanted to see how he recovered today.