It was baseball's 21st perfect game and first since Philadelphia's Roy Halladay threw one against the Florida Marlins on May 29, 2010. It was the third in White Sox's history, joining Mark Buehrle against Tampa Bay on July 23, 2009, and Charles Robertson against Detroit on April 30, 1922.
"This is awesome," Humber said. "I'm so thankful."
With the White Sox lined up on the top step of the dugout, Humber fell behind 3-0 to Michael Saunders leading off the ninth. But he rebounded to strike him out. John Jaso then flied out before Brendan Ryan, another pinch-hitter, struck out to end the game.
Ryan took a checked swing and missed at a full-count pitch, but the ball got away from catcher A.J. Pierzynski. Ryan lingered outside the batter's box for a minute, unsure of umpire Brian Runge's call, and Pierzynski fired to first to complete the play.
Humber, who was involved in a trade for Johan Santana in 2008, fell to his knees went it was over, and his teammates rushed toward the mound to congratulate him.
"I don't know that I dominated them," Humber said. "Obviously the ball was hit at people. I'm thankful for that. It was a well-pitched game. Definitely something I'll never forget."
The right-hander struck out nine and threw just 96 pitches in his first career complete game. He went to a three-ball count only three times.
It was quite a contrast to his first start of the season, when he went 5 1-3 innings and threw 115 pitches in a no-decision against Baltimore on Monday.
Humber was traded from the New York Mets to the Minnesota Twins in the deal for Santana, he bounced around for a couple of season and was acquired by the White Sox on waivers from Oakland in January 2011.
He was 9-9 with a 3.75 ERA in 163 innings last season, his first full season in the majors as a starter.
It was the majors' first no-hitter of the season. There were three last year: Francisco Liriano of Minnesota, Justin Verlander of Detroit, and Ervin Santana of the Los Angeles Angels.
It was the third no-hitter thrown against Seattle. Mark Langston and Mike Witt of the Angels combined on one on April 11, 1990, and Dwight Gooden of the Yankees threw one on May 14, 1996.
Humber struck out the side in the second while cruising through the first four innings in just 45 pitches. Chone Figgins' fly ball to left in the fourth was the first ball to reach the outfield. Dustin Ackley followed with a hard liner to right that Alex Rios reached up and stabbed.
The White Sox moved farther and farther away from Humber as he approached history, leaving him alone as he sat on the bench in the Safeco Field visitors' dugout.
Justin Smoak struck out swinging to start the eighth. Kyle Seager lofted a fly to left that looked momentarily like it had a chance to land, but was caught by Dayan Viciedo. Jesus Montero followed with an easy ground ball to second base, sending the perfect game to the ninth.
Paul Konerko hit his second home run of the season and No. 398 for his career in the second. He also had a run-scoring single in the third.
Mariners starter Blake Beavan (1-2) allowed three runs and seven hits in six innings.
Humber was drafted No. 3 overall by the New York Mets out of Rice in 2004. He reached the majors in 2006 but his career was sidetracked by the elbow injury.
He becomes the latest one-time Mets pitcher who went on to throw a no-hitter elsewhere, a group that includes Nolan Ryan, Tom Seaver, Gooden and David Cone. New York has never had a no-hitter in its 51-year history. The only other team without one is San Diego, which began play in 1969.
Notes: Coming into Saturday, the Mariners were hitting .103 over the last three games with runners in scoring position, with no extra-base hits and eight strikeouts while grounding into three double plays. . Mariners RHP Felix Hernandez has 25 career starts with seven or more shutouts innings. . Seattle reliever Hisashi Iwakuma made his major league debut Friday night, becoming the last player on an Opening Day roster who was not hurt or optioned to the minor leagues to do so. . Rios came into Saturday with an eight-game hitting streak.