On July 6, despite not having been initially selected, Weaver was chosen to replace CC Sabathia on the American League roster for the 2010 All-Star Game due to the latter's ineligibility to pitch. He joined Torii Hunter as the only Halos representing the host club for Angel Stadium's third Mid-Summer Classic, though he did not pitch in the game. The All-Star selection was well-deserved, as Weaver posted the best season of his short big league tenure thus far. Weaver was the major league strikeout champion with 233, besting Mariners ace Félix Hernández by a single strikeout. He also posted career-bests in innings pitched (with 224.1), ERA (3.01), and WHIP (1.07). Weaver's success was not reflected in his win-loss record, however, as he went 13–12 due in part to poor run support. Despite the uncertainty over the role earlier in the season, Weaver embraced and ably fulfilled his new responsibility as the team's ace in 2010. He finished 5th in AL Cy Young award voting.