Werth became the fifth Philadelphia player to drive in eight runs in a game, joining Kitty Bransfield, Gavvy Cravath, Willie Jones and Mike Schmidt.
Werth hit a three-run homer in the second inning, produced the first grand slam of his career in the third and added a solo shot in the fifth.
The power surge backed up the pitching of Jamie Moyer (3-3), who limited Toronto to three runs on seven hits while striking out five in 6 2/3 innings.
The Phillies won for the third time in four outings. Toronto had won its previous four games.
The loss went to David Purcey, who gave up eight runs on five hits in three innings.
The inter-league series celebrates the 15th anniversary of the Philadelphia-Toronto World Series, which ended with a home run by the Blue Jays' Joe Carter in Game 6.