Knuble's performance overshadowed a stellar turn by goalie Martin Biron, who got his third shutout this season and the 21st of his career.
After a scoreless first period, Knuble scored twice in the second and once in the third, giving him 19 goals this season. He scored with assists by six different teammates Saturday.
The much-improved Flyers improved to 23-2-0 when allowing two goals or fewer.
Jonas Hiller yielded three goals on 25 shots for the Ducks, who have been shut out in back-to-back contests. They lost a 1-0 shootout at St. Louis Friday.
It was the first contest between the teams in Philadelphia since March 21, 2002 -- and the Flyers' first home shutout since Oct. 22, 1996, against Anaheim.