Five ahead at the start of another humid day at Pinehurst Resort, the 29-year-old from Dusseldorf left his closest pursuers trailing in his wake as he closed with a one-under-par 69 on the challenging No. 2 Course.
Kaymer, whose first major win came at the 2010 PGA Championship, mixed two birdies with one bogey in the last six holes on a layout where danger lurked at every corner to post a nine-under total of 271, the second lowest ever at the event.
The former world number one, who had struggled for much of 2012 while working on his swing to develop a draw, became the first German to win the U.S. Open and the seventh player to complete a wire-to-wire victory at the year's second major.
After soaking up a standing ovation as he walked along the 18th fairway and on to the green, Kaymer sank a 15-foot putt for par, dropping his putter in delight a few seconds before the ball disappeared into the cup.
"To win one major is already very nice in your career, but to win two, it means a lot more," Kaymer, who took a stranglehold on the championship by firing successive 65s in the first two rounds to lead by six shots, told reporters.
"Even though I don't feel like I need to prove anything to a lot of people, somehow it's quite satisfying to have two under your belt. I played really, really well on Thursday and Friday and that gave me a really nice cushion.
"But I would say it was probably the toughest day that I have played golf today .... especially the first nine. If you have two or three Americans chasing you, playing in America, it's never easy being a foreigner."
Rickie Fowler, who played with Kaymer in the final pairing, carded a 72 to tie for second at one under, level with fellow American Erik Compton, a double heart-transplant recipient who also signed off with a 72 in only his second major appearance.
However, the tournament was Kaymer's to win or lose as he headed into the final round with a commanding lead and he prevented his rivals from making significant inroads as he mixed aggressive golf with careful recovery work as and when needed.
Kaymer, watched by several LPGA Tour players including fellow German Sandra Gal and former women's world number one Yani Tseng, recorded his first birdie of the day after driving the green at the 313-yard, par-four third and two-putting.
Compton birdied the par-five fifth to trim Kaymer's lead to five and the German, playing one group behind, failed to follow suit there when he missed his birdie putt from six feet.
Though Compton faltered with a three-putt bogey from just 15 feet at the par-four seventh, Kaymer also went on to drop a stroke there after missing the fairway off the tee and failing to reach the green in two.
Compton went birdie-bogey to reach the turn in even par before Kaymer struck a superb eight iron to five feet at the par-three ninth and rolled in the birdie putt to stretch his advantage to six strokes.
Kaymer, who gained a major confidence boost from his victory at the elite Players Championship last month, made a mess of the par-five 10th to end up with a bogey, missing the fairway of the tee and finding an awkward lie in a waste area with his second before overshooting the green with his third.
Compton's challenge unravelled as he bogeyed 11 and 12, and Kaymer distanced himself further from the field with astonishing birdie putts at the 13th and 14th, holing out from 15 and 30 feet to storm eight strokes clear at 10 under.
The German could afford the luxury of a bogey at the 16th, where he failed to get up and down from just in front of the green, and did well to save par at the last after his tee shot ended up in a poor lie behind a bush in the native waste area.
"He kind of killed the event in the first two days," Swedish world number two Henrik Stenson said of Kaymer after carding a 73 to finish in a five-way tie for fourth at one over. "He went out and shot two 65s and left everyone in the dust."
England's Justin Rose, who won last year's U.S. Open at Merion, finished in a tie for 12th at three over after shooting a 72, one stroke worse than Australian world number one Adam Scott (69).