Perry, who two weeks ago won the Senior Players Championship, was 10 behind pace-setter Michael Allen at the halfway mark but romped to victory by shooting a 64 in the third round and finishing with a seven-under round at Omaha Country Club.
The previous biggest comeback after 36 holes in a senior major was seven strokes.
"That was by far probably the greatest round of golf I ever played," Perry, a 14-time winner on the PGA Tour, said in a TV interview after his round.
"It all came together today."
Finishing second was fellow American Fred Funk, who shot a final-round 68 for eight-under-par 272.
Another stroke back were Rocco Mediate (66) and Corey Pavin (67) on 273, with Allen a further shot behind after registering a two-over 72 on Sunday.
Perry began the final round two shots behind Allen, but back-to-back birdies from the second hole set the tone for his brilliant finish.
After a bogey at the fifth, Perry made four birdies in a row to make the turn at five-under 30, needing only 10 putts as he took command of the championship.
Perry twice came agonizingly close to winning a major, finishing second at the 1996 PGA Championship and at the 2009 Masters, but never broke through.
In winning the U.S. Senior Open, the 52-year-old became the 11th player ever to win back-to-back senior majors.
(Reporting by Larry Fine in New York; Editing by Gene Cherry)