Another wayward drive and bogey at the ninth left Lowry on the same score as he started the day, 16-under par, as he turned for home.
With favorite son Rory McIlroy having failed to make the cut at Northern Ireland's first major since 1951, Lowry filled the void just fine. Fleetwood got within three strokes after the first hole but never got any closer, finishing with a 3-over 74.
He had a two-shot lead on Holmes but gave them back on the last few holes after steaming to the turn in 31, but he would have accepted his final position at any point. He's seven shots back of the leader, Shane Lowry, who's at -16 for the weekend. He tapped in to pick up another shot at No. 4, before birdies at Nos.
Also watching proceedings intently were Tommy Fleetwood and Lee Westwood, in the penultimate group out, as they looked to strengthen their chances of becoming the first Englishman to win the Open since Nick Faldo in 1992.
Out of the mix is four-time major champion Brooks Koepka, who had a steady stream of mistakes. Fowler's tee shot at 1 was slightly off line and initially bounced in bounds before hitting a marshal and bouncing out of bounds.
Holmes had two straight bogeys on the back nine, didn't make as many putts as the opening two rounds, but otherwise was solid for a 69.
After missing the cut at last year's Open, for the fourth time in succession, Lowry slumped to a ranking of 92nd.
Graeme McDowell, Portrush-born and the only remaining Northern Irishman left in the field, went out in a level-par 36 after three-putting the par-three sixth cancelled out his birdie at the second and he remained one over.
Yet in golf things are never that simple and that fateful Sunday just outside of Pittsburgh was dragged back to the fore for Lowry this week.
In the first major of the season, at the Masters in April, Augusta National Golf Club officials moved up the Sunday tee times and had players tee off on Nos. Easily the man from the American MidWest, and not the supposed links and bad weather specialist from County Offaly. Sunday's tee times at Royal Portrush have been moved up with the threat of severe weather moving in Sunday evening. He doesn't figure to have a big advantage, though.
"You can easily get frustrated because Shane is doing so well and how well he's playing", Fleetwood said.
He damn near birdied No. 18 from halfway to yonder, and when that little rascal took up shop right next to the cup, Lowry had the 12th 63 in Open history, one shy of the record 62 from Branden Grace in 2017 on the Saturday at Royal Birkdale.
Lowry is coming off the best day of his career when he shot 8-under 63 before a raucous gallery at Royal Portrush.
But Lowry sank a confidence-boosting six-footer to salvage a bogey and looked every bit a champion for the next hour after that in the intermittent driving rain, avoiding the punishing rough and knee-high rough waiting to gobble up errant shots.
Behind him, Lowry, who teamed with McIlroy for Irish golf when they won the European Amateur Championship in 2007, kept widening the gap. He says it's natural to consider what's at stake, and the more he tries not to think about it only means he'll think about it more.