The Kansas City Royals' punchless offense couldn't touch him.
"Getting ahead early and getting the lead, we just kept putting on and putting on," said Santiago, who has taken over injured starter Gavin Floyd's spot in the rotation.
"You want to go out every inning and show them you're fighting," he said. "They score runs and you want to get them back in so they keep scoring."
Viciedo's three-run shot capped a five-run third inning, and De Aza's two-run homer in the sixth put the game away. Tyler Flowers was the only member of the White Sox starting lineup without a hit against Jeremy Guthrie, reliever Bruce Chen and the Royals' roughed-up bullpen.
"It was a good first inning," Chicago manager Robin Ventura said, "and I think the approach all night, and against those two guys, having Guthrie and Chen in there at the same time, as tough as they've been on us, you're exorcising some curse or something. It was good."
It was easily Santiago's best performance since going seven scoreless innings May 7 against the New York Mets. It also helped the scuffling White Sox get back on track after losing 17 of 22 and dropping a season-high 12 games below .500.
The left-hander gave up just three hits and a walk, and Eric Hosmer's homer in the sixth represented the only run Santiago (3-5) has allowed to the Royals in 19 1/3 career innings.
"He got that early lead. He was pounding the strike zone and letting his defense do the work," Hosmer said. "He had a lot of run support and he was feeling confident. When you have that lead you can tell the hitter, 'Here it is. Hit it.'"
On a warm, windy night at Kauffman Stadium, Guthrie (7-5) walked three of the first five batters he faced, and the bases-loaded free pass that he issued to Paul Konerko brought in the game's first run. Conor Gillaspie added a sacrifice fly later in the first to make it 2-0.
The real trouble for Guthrie came in the third, when Alexei Ramirez led off with a single and Alex Rios doubled over the head of Alex Gordon in left field. Adam Dunn's single drove in another run, and Gillaspie's single knocked Guthrie from the game.
Viciedo greeted Chen with a three-run shot to give the White Sox a 7-0 lead.
"I just couldn't find the strike zone," Guthrie said. "I created a mess in the first inning and gave up a bunch of base hits in the third."
Guthrie wound up allowing six runs on five hits and three walks in 2 1/3 innings, his shortest start since going the same distance for the Orioles on July 7, 2009. It was his second straight shaky outing, too -- he allowed five runs over seven innings Saturday night at Tampa Bay.
All the more puzzling is that Guthrie had been having success against the White Sox. Since joining the Royals last year, the right-hander had been 3-0 in six starts against their AL Central rivals, giving up just two earned runs in 44 2/3 innings.
Guthrie had given up that many Friday night before escaping the first inning.
"He just didn't have it," Royals manager Ned Yost said. "It was one of those nights when he didn't have much going for him."
De Aza's two-run homer in the sixth made it 9-0, the most runs that the Royals' stingy pitching staff had allowed since an 11-6 loss to the New York Yankees on May 10. It was also the most runs the White Sox had scored since beating Toronto 10-6 on June 10.
"That's how this team is, going back to last year," Dunn said. "But you could see it, a little sigh of relief. You get a couple hits and you get a little excitement on the bench."
The White Sox recalled RHP Brian Omogross from Triple-A Charlotte before the game. ... Major League Baseball announced the Royals will make up their May 2 game against Tampa Bay that was snowed out on Aug. 26 at Kauffman Stadium. The first pitch will be at 1:10 p.m. CT. ... LHP Jose Quintana takes the mound Saturday against Royals RHP Wade Davis.