Federer posted a 6-0, 7-6 (9-7) victory over the Serbian superstar, adding the 2012 Cincinnati crown to his wins at the event in 2005, 2007, 2009 and 2010.
The Swiss icon unleashed eight aces while closing out the second-set tiebreaker with consecutive forehand winners to improve to 16-12 against Djokovic, including a 4-3 mark in title matches.
It marked Federer's sixth title of the year and 76th of his career.
Djokovic, meanwhile, fell in the Western & Southern Open final for the fourth time in five years. He retired with a sore shoulder in last year's finale, handing a win to Andy Murray.
The Serb's loss came after last week's victory at the Rogers Cup.