Halladay (20-11) improved to 5-1 in six starts against the Yankees this season and posted his second career 20-win season. The right-hander went 22-7 with nine complete games in 2003, when he won the AL Cy Young award.
Halladay, who joined Cleveland's Cliff Lee as a 20-game winner, gave up two runs and six hits. He walked one and struck out five, giving him 206 for the season, a career-high.
Wells hit a two-run homer in the third and added a two-run single in the fourth as the Blue Jays closed out the home portion of their schedule with a 47-34 record.
Carl Pavano (4-2) allowed five runs and eight hits in 3 2-3 innings, his shortest outing since coming off the disabled list last month.
The Yankees opened the scoring in the third when Brett Gardner doubled and scored on Robinson Cano's single.
Wells put Toronto ahead with his 18th homer in the bottom half, and the Blue Jays chased Pavano with a three-run fourth.
Joe Inglett hit an RBI single, Marco Scutaro reached on a fielder's choice and Alex Rios walked before Wells ended Pavano's night with a two-run single to left.
New York got one back in the fifth, with Cody Ransom scoring when Francisco Cervelli grounded into a double play, but the Blue Jays added two in the bottom half against reliever Dan Giese. Scott Rolen singled before consecutive doubles by Travis Snider and Gregg Zaun made it 7-2.
Scutaro made it 8-2 with an RBI single in the seventh against Humberto Sanchez.
The Yankees held Johnny Damon, Derek Jeter and Alex Rodriguez out of the lineup, with Ransom, Wilson Betemit and Melky Cabrera starting instead. Cervelli made his major league debut behind the plate. New York manager Joe Girardi said he will put his regulars back in the lineup when the Yankees open a three-game series at Boston on Friday.
Notes: Toronto manager Cito Gaston signed a two-year contract extension before the game, and Blue Jays president Paul Godfrey confirmed that general manager J.P. Ricciardi will return in 2009.
... Yankees RHP Mariano Rivera returned to New York Thursday for season-ending medical tests. Rivera will rejoin the team in Boston on Friday. ... New York and Toronto split the season series 9-9. ... The crowd of 44,346 pushed Toronto's total attendance to 2,399,786.