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The pair are on eight under par for the tournament, one shot clear of Englishmen Tommy Fleetwood and Lee Westwood.
Meanwhile New Zealand's Ryan Fox blew out with a four over par 75 to slip from a share of third to a tie for 59th, nine shots off the pace.
He shot an Open record 29 on the back nine yesterday to card an opening round three under par 68, but four bogies and a double bogey undid him in today's second round.
Masters champion Tiger Woods followed his first-round 78 with a battling 70 to miss the cut.
Overnight leader Holmes was first into the clubhouse at eight under after a 68, with five birdies and two bogeys.
But it was the performance of Lowry that had the crowd in raptures, the Irishman birdieing four of the first five holes.
At one stage he was 10-under-par but despite a couple of dropped shots, including a bogey at the last, he was delighted with his second consecutive round of 67.
"I had a great time today," Lowry said.
"God it was just unbelievable. It was one of those days where I found myself pinching myself out there. I can't explain how good the crowds were. It was a day that I'll remember.
"I'm a bit disappointed with the finish but I'm in a great position after two rounds."
Fleetwood and Westwood both shot 67.
Fleetwood, chasing his first major win, birdied the last hole and said minus seven was right where he wanted to be going into the weekend.
"I hit a few ropey shots but overall I played a lot of great shots," Fleetwood said.
"To be up there after two rounds at the Open, it's great."
Westwood produced a bogey-free round of 67, all four of his birdies coming in a back nine of 31.
Koepka described his round as "a little sloppy" but is right there in contention, the same as Spieth, who threatened to go really low when he went birdie, birdie, eagle, birdie from the fifth hole.
But the 2017 Open champion bogeyed the ninth and survived an up and down back nine to stay five-under.
Woods, who shot seven-over-par in round one, clawed back three shots but bogeyed the last two to miss his chance of making the weekend.
"I'm going to have my hot weeks," said Woods, who struggled with his back.
"I'm going to be there in contention with a chance to win, and I will win tournaments.
"But there are times when I'm just not going to be there and that wasn't the case 20-some-odd years ago. I had a different body and I was able to be a little bit more consistent."
Defending champion Francesco Molinari picked up three shots in his first 11 holes to get back to level par, with six to play.
And McIlroy birdied the third, seventh, 10th and 11th to give himself a chance of being around for the final two rounds.