Halladay pitched his first shutout in the National League, against the Atlanta Braves on April 21, becoming the first pitcher to reach four wins in the 2010 season. On May 1, Halladay pitched his second shutout of the season, limiting the New York Mets to three hits and striking out six.
On May 29, 2010, Halladay pitched the 20th perfect game in MLB history against the Florida Marlins in Miami, retiring all 27 batters and striking out 11, allowing no hits, runs, walks, or errors. This was the first time in the modern era that two pitchers (Dallas Braden of the Oakland A's and Halladay) had thrown perfect games in the same month and that multiple perfect games had been achieved in the same season. When Halladay's former manager, Cito Gaston, called to congratulate him, Halladay was unable to take the call because he was busy with the post-game media frenzy.
On August 24, 2010, to commemorate his perfect game, Halladay presented around 60 Swiss-made Baume and Mercier watches he had purchased to everyone in the clubhouse. The watches were presented in brown boxes that bore the inscription: "We did it together. Thanks, Roy Halladay." Additionally, the back of each watch was engraved with the date of the game, the line score, and the individual recipient's name.
On October 6, 2010, in his first postseason appearance, Halladay pitched a no-hitter (his second of the season), against the Cincinnati Reds in the first game of the National League Division Series (NLDS).
In May, Halladay was named the 2011 winner of the John Wanamaker Athletic Award, by the Philadelphia Sports Congress, based on his 2010 season. In June, Halladay was presented the Best Major League Baseball Player ESPY Award, for his performance since June 2010.