By Andrew Both
In his 162nd tournament tour appearance, Rose carded a brilliant six-under-par 66 final round to storm to a three-stroke victory at Muirfield Village.
He finished at 18-under 270 and overnight leader Rickie Fowler (73) was runner-up on 15 under.
Rose, 29, made his name when as a 17-year-old amateur he finished fourth at the 1998 British Open.
He won five times around the world before his breakthrough victory in the United States.
"I've had a few close calls," he told CBS television. "It's nice to have the hard work pay off."
Tiger Woods (72) finished equal 19th on six-under in his last start before the U.S. Open at Pebble Beach next week.
(Editing by Ed Osmond)