Sale, 4-0 with a 1.18 ERA in his last five starts, hasn't allowed a run in 23 straight innings, and his six-start streak of lasting at least seven while allowing fewer than three earned runs is the longest by a White Sox starter since Mark Buehrle's seven-start run in 2007.
Chicago announced Tuesday, though, that the left-hander had been scratched from this start due to mild tendinitis in his shoulder.
Santiago (1-2, 2.78 ERA) will take the hill in Sale's place. He has gone 1-1 with a 2.95 ERA in four starts since making his first May 2, but he walked four and gave up three runs in 3 1-3 innings of Chicago's 12-9 loss to the Los Angeles Angels on Saturday.
He said he noticed his high pitch count in the fourth before being removed.
"I'm never like that. I go inning by inning. If I go five, if I go seven, it doesn't matter," Santiago said. "(I'm) just trying to make better pitches."
The only time Santiago, who has yet to make a start at home this season, has faced Boston was July 18, when he allowed two runs in three innings of relief in Chicago's 10-1 loss.
He seeks a better performance this time around for the White Sox (21-23), who have won six of nine after Jose Quintana took a no-hitter into the seventh inning of Tuesday's 3-1 victory. David Ortiz's one-out single in the seventh marked the Red Sox's first hit.
"Our starting pitching's really good," said Jeff Keppinger, who hit a two-run homer. "Every game, we're in it. It's just a matter of if we can get that big hit."
Alex Rios went 2 for 4 with an RBI double and is batting .391 during a career-best 16-game hitting streak. Rios, though, is 2 for 13 off Buchholz, who seeks his first victory in four outings.
Buchholz (6-0, 1.78) won his first six starts behind a 1.01 ERA, but he's posted a 3.43 ERA over his last three. He struck out nine and gave up two runs in seven innings of a 3-2, 10-inning win over Minnesota on Friday, marking the sixth time he's finished with at least eight strikeouts.
"Team wins. That's what this game's about. There's absolutely no disappointment (not earning a decision)," said Buchholz, whose ERA is best in the AL.
The right-hander also didn't pick up a victory despite a stellar start the last time he faced the White Sox, giving up one run in eight innings of a 3-1 win July 19. He's 1-1 with a 1.71 ERA over his last three outings against Chicago.
The Red Sox (27-19) have dropped the first two games of this set after winning five straight. Ortiz is 1 for 7 after entering the series batting .429 during a seven-game hitting streak.
Boston outfielder Shane Victorino didn't play Tuesday because of tightness in his left hamstring and is day to day.
The Red Sox have lost three straight road meetings with the White Sox after winning the previous five.