Humber debuted with the White Sox in their third game in relief. He made two pitches, both of which resulted in hits and base runners that came around to score. With Jake Peavy injured at the start of the 2011 season, the White Sox gave Humber the opportunity to pitch in their starting rotation. On April 9, 2011, Humber won his first start with the White Sox, pitching innings and only allowing one run. Humber surprised the White Sox with his strong performance. On April 25, in the sixth start of his career, he took a no-hitter into the seventh inning against the New York Yankees at Yankee Stadium, but with one out Alex Rodriguez singled up the middle. He finished with seven scoreless innings. He took a no-hitter into the sixth inning against the Washington Nationals on June 26, but ended up earning a 2–1 loss when he surrendered a seventh inning home run to Danny Espinosa. In early July, when he led the major leagues with innings pitched and held an 8–4 record with a 2.69 ERA, he seemed like a probable selection for the 2011 Major League Baseball All-Star Game. In mid-July, the White Sox switched to a six-man rotation. By early August, Humber was in a slump. Humber denies the extra rest affected his pitch command. He spent time on the disabled list with a facial bruise after Kosuke Fukudome lined a baseball into his face above the right eye on August 18. After he was hit, he was very concerned for his wife: "I thought, 'I've got to get up because she's in the stands,'" Humber said. "As soon as I went in clubhouse, I asked one of the guys to call her to make sure she knew I was OK.", adding "My main concern was cheering up my wife." He appeared in one rehabilitation start for the Charlotte Knights of the Class-AAA International League. Humber pitched seven scoreless innings in his major league return. Humber completed his first full season as an MLB starting pitcher with a 9–9 win–loss record with a 3.75 ERA in 163 innings.