Scherzer (3-1) won his third straight start, allowing four hits while striking out seven to become the first pitcher in team history with at least seven strikeouts in each of his first six starts.
He also became the first in the majors to do it since Tim Lincecum began the 2010 season with at least six strikeouts in his first seven starts.
But it was the three walks and 105 pitches that gnawed at the reigning AL Cy Young Award winner.
"They fought me all the way through the whole at-bat," Scherzer said. "I just thought I could have been a little more efficient so I could have pitched deeper into the game."
Scherzer beat the White Sox for the second straight time, following up his April 24 win when he went six innings and allowed two runs in a 7-4 victory.
He also helped Tigers win for the fourth time in five games, and shut down the powerful White Sox offense for the second straight day.
"Yeah, we missed out on a couple of opportunities today and yesterday too, but those guys are pretty good pitchers and have been for a while," White Sox catcher Tyler Flowers said.
"They do some good things in those situations and get the job done. We just have to find a way to battle through on some of those and get some runs across."
On Tuesday, Justin Verlander and two relievers held the White Sox to seven hits in a 4-3 Detroit win.
Scherzer and the Tigers continued that Wednesday against a team that started the day first in the American League in runs and second in home runs and slugging, coming within one out of a shutout.
"There's 29 other managers that would like to be able to do that," Detroit's Brad Ausmus said of starting Verlander and Scherzer on consecutive days.
Chicago's Robin Ventura is certainly one of those managers. As with Flowers, he heaped praise on Scherzer.
"He's great, he's always tough. You get some guys on, you get opportunities and that's when good pitchers really show their stuff. He did that today," Ventura said. "We at least got him a high pitch count and he couldn't get eight or nine innings. But, he's just tough."
The Tigers got all the runs they needed in a four-run fourth, when Detroit scored four times against Hector Noesi (0-2). Bryan Holaday capped the rally with a two-run double.
Noesi, making a spot start for Chicago, went 3 2/3 innings, allowing four runs and five hits. He breezed through the first three innings, but ran into trouble in the fourth in his first start of the season.
"We don't know much about the guy, and I don't think he has been extended that far so it may have been a combination of the hitters getting a chance to see him a few times and also maybe because he hadn't been as deep into a game this year," Ausmus said. "He could have been getting a little tired as well."
The White Sox challenged Scherzer as well, but left seven runners on against the Tigers righty.
"I'm very cognizant of what they're able to do and always willing to give them credit," Scherzer said. "Today I thought they did a good job of battling me but when push came to shove I thought I was better."
The Tigers announced that left-hander Robbie Ray will make his major-league debut Tuesday in Detroit against the Astros. Ray, 22, was acquired this offseason from the Nationals as part of the trade that sent starter Doug Fister to Washington, and will start in place of injured starter Anibal Sanchez. Sanchez is on the disabled list with a laceration on his right middle finger and threw from flat ground prior to Wednesday's game. . C Alex Avila missed his second straight game with back spasms. . Robin Ventura said LHP Chris Sale is "feeling better" but a rehab start is a possibility if his recovery continues to be extended. Sale has been on the disabled list since April 22 -- retroactive to April 18 -- with a flexor muscle strain in his left arm. Ventura also said RHP Felipe Paulino (right rotator cuff inflammation) will have a rehab assignment coming up "pretty soon."