Two ahead overnight in the second major championship of the year, Lowry birdied two of his last four holes to get to seven-under 203 with a first grand slam title looming in his sights.
The burly 29-year-old from Clara in County Offaly did well to salvage a par at the last, coolly sinking a 10-footer to card a five-under 65 on one of the toughest golf courses in the world before pumping his fist in delight.
"It was a really good morning's work for me and I am really looking forward to getting out there in the afternoon and seeing what I can do," said Lowry, who won the biggest title of his career at the 2015 WGC-Bridgestone Invitational.
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"It's one of the best rounds of my career, a 65 on this course. I just need to stay in the moment, stay patient. It's going to be tough. I mean, let's be honest, I've already visualized myself winning.
"Even out walking around the course this morning ... you do think about that," said world number 41 Lowry, a three-times winner on the European Tour who tied for ninth in last year's U.S. Open at Chambers Bay.
Dustin Johnson, the tournament leader after 36 holes, carded a 71 to share second place with fellow American and PGA Tour rookie Andrew Landry, the surprise first-round pacesetter who drained a 45-foot birdie putt at the last for an even 70.
"I've got a lot of confidence in my game right now," said Johnson, a nine-times champion on the PGA Tour who missed a three-foot putt at the final hole to hand last year's U.S. Open to Jordan Spieth.
"I feel like I'm swinging really well. Just got to go out and play a good, solid round of golf and see what happens."
England's former world number one Lee Westwood (69), who like every other player in the top eight at Oakmont after 54 holes is seeking a first major title, and American Daniel Summerhays (69) were a further stroke back at two-under.
The only other player under par after the third round holes was South African Branden Grace, who had surged into contention with a six-birdie 66 on Saturday to set the clubhouse lead overnight at one-under 209.
Two strokes behind Grace in a tie for ninth was Australian world number one Jason Day, who completed a matching 66 on Saturday that included an eagle at the par-five fourth.
Lowry made an ideal start on a sunny morning at Oakmont, hitting his approach at the par-four 15th to 10 feet and sinking the birdie putt to extend his lead to four shots at six under.
That advantage was soon cut to three when the long-hitting Johnson, playing one group behind, followed suit by rolling in a 30-footer at the 15th to get to three under.
Lowry pocketed his second birdie of the day at the driveable par-four 17th, his tee shot settling just above a bunker 50 yards short of the hole from where he played a delicate chip to seven feet and sank the putt.
(Editing by Pritha Sarkar)
