Youkilis, who had three hits, sent his second career slam into the right-field bullpen during a five-run third inning against Humber, who was making his first start since pitching a perfect game in a 4-0 victory at Seattle on Saturday.
"I'm having better at-bats and doing little things here and there," Youkilis said. "I look at it as a long season, and you're going to go through stuff. Hopefully the bad at-bats are a thing of the past."
Youkilis singled and scored in the fifth and added an infield single in the eighth. He scored twice.
It was an encouraging sign for a hitter that entered the game batting .204. The grand slam was his second homer of the season and just his second in his last 28 games dating to Aug. 14, 2011.
The resurgent Red Sox have scored 34 runs in winning their last four games, a streak that comes on the heels of a five-game skid.
"The offense is playing extremely well," manager Bobby Valentine said. "A combined effort, no one trying to do too much. That's good offense. That's playing baseball the right way."
Boston starter Felix Doubront (1-0) wasn't sharp but picked up his first big league win since Aug. 10, 2010. He allowed five hits and three walks, threw a wild pitch and hit a batter with a pitch, but limited the White Sox to three runs in six innings.
Junichi Tazawa tossed three scoreless innings for his first major league save.
"When a guy gets his first when you're managing, it's a special night," Valentine said. "Felix got his first win, Tazawa got his first save . it's a good little memory for me, and them, too."
It didn't take long for Humber (1-1) to falter. He walked leadoff batter Mike Aviles in the first, snapping his streak of 29 straight batters retired.
One out later, the right-hander allowed a single to Dustin Pedroia, a dribbler up the third-base line that was the first hit off Humber since Nick Markakis' one-out double for Baltimore in the fifth inning of the Orioles' 10-4 victory at Chicago on April 16.
"I got a lot of pitches up over the plate," Humber said. "To a team like that, they make you pay for it."
Humber was tagged for a career-high nine runs and eight hits in five innings. The nine earned runs he allowed after his perfect game were a record, topping the eight given up by Jim "Catfish" Hunter after his perfecto for Oakland in 1968. Humber also didn't fare much better than the previous four pitchers to throw a perfect game since 2000 (Roy Halladay, Dallas Braden, Mark Buehrle and Randy Johnson allowed a combined 26 hits in 28.1 IP in their next start with a combined ERA of 4.13.)
"This game will humble you, man," Humber said. "It will make you feel good one day and make you feel real bad the next. You've got to take every game as its own game."
Johnny Vander Meer remains the only major league pitcher to throw consecutive no-hitters, accomplishing the feat in 1938 with Cincinnati.
It's been a hectic week for Humber, who did a segment on David Letterman's show among many media-related appearances this week. Also, his wife Kristan is expecting the couple's first child in the next couple of weeks.
"I stayed with my normal routine," Humber said. "I did my best to eliminate the distractions. I felt like I was focused on the game.
"I don't think anything that happened Saturday affected tonight," he added. "It was just a bad day. I'll just chalk it up to one of those days and hopefully next time will be better."
After throwing just 96 pitches to complete his masterpiece, Humber twice needed more than 30 pitches to get through an inning. He threw 92 pitches over the first four innings.
Saltalamacchia followed Youkilis' slam with a home run just inside the right-field foul pole. He added a two-run shot in the fifth off Humber, his fourth homer of the season.
"(My swing) feels good right now," Saltalamacchia said. "Right now I'm just trying to put good wood on the ball and stay consistent with my approach."
Humber allowed three walks and three homers. His ERA rose from 0.63 to 4.66.
"We had our reports on watching Phil," Youkilis said. "He's a guy who's going to throw strikes and go at you. You have to be ready to hit."
Chicago's Dayan Viciedo broke out of a 1-for-16 slump with two hits, including a leadoff homer in the fourth. All three of his RBIs this season have come on solo homers.
Marlon Byrd started in center for the Red Sox in his first game in Chicago since being acquired from the crosstown Cubs on Saturday. ... Andre Rienzo, a pitcher in the White Sox farm system, was suspended for 50 games after testing positive for a banned substance.