That pitch also has produced quite a few surprised reactions from hitters who have been consistently fooled by the offering.
"I've talked to a bunch of guys just in between pitches, and they were like, 'Whoa, what was that thing?'" said White Sox catcher Josh Phegley, who worked with Santiago at Double-A Birmingham in 2011. "It surprised them every time.
"It will fade to the outside corner [against a right-handed hitter] and they will be buckling. Out of his hand, it's coming up and in and they have no idea. It's like a right-handed curveball and a left-handed changeup in the same pitch."
Santiago, 24, entered Tuesday's scheduled off-day for the White Sox as a veritable lock to break camp as one of the team's seven relievers. He threw a scoreless inning against the Reds during Monday's 1-0 loss at Camelback Ranch, giving him six without allowing a run this spring, while striking out six.
Credit for Santiago's inception of the pitch goes to Angel Miranda, a fellow southpaw who started and relieved for the Brewers from 1993-97, and showed Santiago in Puerto Rico during his first year of winter ball in 2008.
"He said left-handers used to throw it a lot," said Santiago of Miranda's instruction. "He was one of the last guys who threw it. He was like, 'You have the perfect arm slot for it.'
"I didn't really have a changeup at the time, so it was like, 'Why not? Let's try it.' It kind of came along more as a changeup and made my changeup a lot better. Over time, I got to the point where I could get my arm into that motion where I could turn it over pretty well."
Strangely enough, the screwball didn't make its way into a game for Santiago until 2010, once again during winter ball in Puerto Rico, at the encouragement of one of his coaches. The plan was to only throw it against right-handed hitters, and the results were too good to ignore.
"There was big drop to it," said Santiago. "It was kind of like a curveball. It had some fade and drop."
Against right-handed hitters, the pitch goes from "in to out" as Santiago explained and as Rangers slugger Nelson Cruz witnessed firsthand on a called third strike during a first-week Cactus League game. From the left side, Santiago's screwball looks like a right-handed curveball.
While Santiago seems to be the only Major Leaguer employing the screwball, it's not a pitch like the knuckler that could be used 70 or 80 times during a 110-pitch outing. Santiago said that a right-handed-heavy lineup is more conducive to the screwball, but he still would only throw 20 or 25 out of 110 pitches.
"I'm not trying to throw it every pitch," Santiago said. "If I throw four in a row, they can pick up the spin or something like that. I try to get them off guard with it and try to throw the fastball or a little slider there and get the big drop of velocity and spin on them."
"Sometimes in the outfield during batting practice, I mess around with him and try to throw and it's impossible," Phegley said. "I've never seen a screwball from anyone. When you see it, you can kind of read it. But you would never expect that kind of break and motion from a pitch from a left-handed pitcher."
After being selected in the 30th round of the 2006 First-Year Player Draft, Santiago made 129 of his first 130 appearances out of the bullpen for Bristol, Class A Kannapolis and Class A Winston-Salem. He started 23 games for Winston-Salem and Double-A Birmingham in 2011, before pitching 5 1/3 scoreless innings in relief for the White Sox, giving up just one hit.
His impressive debut with the White Sox and continued success in Spring Training has caught the eye of the higher-ups in the organization.
"You know, we may take a [Chris] Sale approach with him," said White Sox general manager Ken Williams of Santiago, who also could work as a late-inning left-hander. "We might keep him in the bullpen and then look to start him down the line."
In physically illustrating how to throw the screwball, Santiago points out that he grabs it the same way as his changeup. He just turns it over a lot more, trying to get his thumb and middle finger underneath the ball as much as he can.
Having that extra movement and change in velocity from his fastball has made a big difference in attacking hitters for Santiago, who has a career 3.65 ERA over 153 Minor League games. And that screwball movement leaves hitters stunned but not speechless.
They realize there's nothing screwy about Santiago's success.
"When I threw it for the first time in Puerto Rico, where everyone knows everyone, I would get verbal reactions from people," Santiago said. "Hitters are yelling, 'What's that?' or, 'What are you doing?'
"Here you can see faces if you are paying attention. I saw a few guys, when they took a swing, smile and look like, 'What am I supposed to do with that?' They said it's something funky."