Santiago allowed one hit over six innings and two relievers finished the job as the Winston-Salem Dash blanked the Salem Red Sox, 5-0.
Selected by the White Sox in the 30th round of the 2006 Draft, Santiago (2-2) had his bid for a no-hitter spoiled in the sixth when James Kang dropped a one-out single into center. He struck out Peter Hissey and retired Shannon Wilkerson on a pop fly to end the inning.
"Everything was on today," Santiago said. "The only thing we changed up we worked [inside] tonight. My changeup was working for strikes, my slider was over for strikes to lefties and righties and my fastball was the best it's been all year."
The 23-year-old left-hander, who struck six, thought he had a chance at a no-hitter, even after Kang made contact in the sixth.
"He was out in front, off the end of the bat and he blooped it in there," Santiago said. "It was tough to see out there, we had some fog. I thought it was going to be an easy, nice play but when I saw him running hard I thought, 'Oh, no.'"
Santiago has pitched well since getting off to a rocky start. Over his last two outings, the New Jersey native has lowered his ERA from 4.88 to 3.75. He was 0-2 with a 5.68 ERA in four starts in April.
"I got through the bump in the road early," Santiago said. "I've been working fastballs in. And as long as I get it in, it's been working pretty well."
Addison Reed and Taylor Thompson followed Santiago with three perfect innings, with Reed fanning one over two frames.
"They came in and attacked the zone," Santiago said. "I came out to the dugout and watched them and it was awesome."
Ian Gac hit his Carolina League-leading 11th homer for the Dash, while Jake Oester and Kyle Colligan each plated a pair of runs.