The Mesa starter allowed one hit over five shutout innings, but the Solar Sox could not hold the lead, surrendering four runs over the final two innings to give Scottsdale a 4-3 win in the Arizona Fall League.
Santiago, a right-hander finishing up his sixth professional season with Los Angeles, struck out five and walked two, allowing just one single in the second to Pirates first baseman Matt Curry.
"I feel ... comfortable. Every pitch was working, and I thank God I got good defense," Santiago said. "I feel great."
The Dodgers' 2007 16th round pick threw 41 of his 70 pitches for strikes, turning in 1-2-3 frames in each of his final two innings.
The first three frames, though, weren't as smooth -- Scottsdale managed to get the leadoff man on base in all three, but Santiago got some help defensively to stay unblemished. In the first, top Giants prospect Gary Brown began the game with a walk but was thrown out trying to steal second by Tigers backstop James McCann.
Santiago walked leadoff man Chris Dominguez (Giants) an inning later. But after Curry singled, he retired Adalberto Santos (Pirates) and Randal Grichuk (Angels) before Dominguez was thrown out at third.
Angels prospect Kaleb Cowart reached on shortstop Jiovanni Mier's fielding error to start the third, but Santiago got Alex Monsalve (Indians) to roll into a double play before whiffing Brown to end the frame.
"We were just trying to establish my fastball and make them hit the ball instead of swings and misses," Santiago said. "I got a lot of ground balls, my defense helped me out a lot. My catcher got the man on second and I got that big double play.
"Mier made an error, and the next pitch, I told him, 'Be ready for another grounder.' He turned another ground ball into a double play."
After putting together the best season of his career -- going 6-5 with a 3.69 between Class A Advanced and Double-A -- Santiago struggled in his first two starts in the Fall League, giving up a total of seven runs over six innings. He walked five in a three-inning outing on Oct. 18, after which he focused on tightening up his mechanics and streamlining his delivery.
"I was watching video and I walked a couple guys in the first two games, I was being lazy with my arm," he said. "I adjusted and I felt great and it worked out the way I wanted to.
"When I come set in the windup, I was getting late with my body. I started do that same thing today and I felt uncomfortable, so I'm working on being compact with my arm. I went from the full windup to keeping my arm under my belt."
Santiago left with a 2-0 lead after Orioles' No. 3 prospect Jonathan Schoop reached on a fielding error by shortstop Joe Panik (Giants) in the second that scored Aaron Westlake (Tigers). Schoop then came home on a double by Mier, Houston's first-round Draft pick in 2009.
Mesa added another on an RBI triple by Rafael Ynoa (Dodgers) in the fifth, but a solo homer by Santos in the eighth followed by Dominguez's three-run shot in the ninth sealed a comeback victory for the Scorpions.
The loss was the eighth straight for the Solar Sox.
Danny Wild is an editor for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.