The 29-year-old dominated the field on the final day to win by eight shots as he ended the round with a one-under-par 69.
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He becomes the first German winner of the tournament and the fourth European winner in five seasons.
The former world number one had taken a five-stroke lead going into the final round, despite carding a two-over-par 72 on day three of the tournament.
The gap was temporally reduced to four when he bogeyed the seventh, as Erik Compton made birdie at eight.
A birdie at the ninth extended his lead to six shots at the turn after a bogey from Compton, before he eased to victory over the back nine.
His previous win at the majors came in the 2010 PGA Championship in a three-hole playoff over Bubba Watson.
Victory for Kaymer means that he is first player to have won at the US Open and The Players Championship in the same year.
Meanwhile, Phil Mickelson will continue his long wait for a first Open win for the career Grand Slam after a final round 72, while 2011 winner Rory McIlroy ended on 73 leaving him six-over for the tournament.