The Irishman claimed his sole major victory at Portrush five years ago and should relish more wet and windy weather to come on the west coast of Scotland.
Lowry overcame a dramatic double bogey on the 11th on Friday to move to seven under par, two clear of Englishmen Justin Rose and Daniel Brown.
A former US Open and Olympic champion, Rose had to go through qualifying to secure his place in Troon but produced a stellar round of 68 in the worst of Friday's blustery weather conditions.
Brown, by contrast, is taking part in his first-ever major and the world number 272 showed remarkable poise to handle the spotlight in his second round after a six-under round on Thursday took him to the top of the leaderboard.
"I don't know what I'm going to reach in and grab in the memory bank but it will be very beneficial that I've done this before," said Lowry.
The biggest threat to Lowry's dream of winning the event for a second time could well come from world number one Scottie Scheffler, who sits five shots back in a share of fourth.
Scheffler has already won six times this year, including his second Masters in April.
But he is yet to transfer that form across the Atlantic with his best British Open showing so far a tie for eighth in 2021.
"I'm not sure Scottie Scheffler is too worried about anyone with the form he's in," added Lowry.
"He's obviously on the leaderboard, and he's one person that people are going to be talking about."
Missing McIlroy backs Lowry
World number three Xander Schauffele is also among the chasing pack at one under par.
But the wild Ayrshire winds blew a host of star names off course in the opening two days, causing them to miss the cut.
Rory McIlroy was among seven of the world's top 12 who failed to make the weekend.
Instead, the world number two is resigned to a supporting role for the final two rounds as he cheers on close friend and Ryder Cup team-mate Lowry.
"He relishes these conditions," said McIlroy. "The Open Championship is his favourite tournament in the world. He gets more up for this than anything else.
"I'm looking forward to cheering him on and hopefully him getting his second (Claret) Jug."
US Open champion Bryson DeChambeau and world number four Ludvig Aberg were among the others to miss out to leave the leaderboard wide open for the final two rounds.
Patrick Cantlay is among the small pool of 10 players to so far break par, at one under.
Joaquin Niemann, who has been in fine form on the breakaway LIV circuit, is at level par despite dropping five shots at the par-three eighth on Friday.
The Chilean found three different bunkers around the famous Postage Stamp green to ruin his chances of starting Saturday in the final group.
Two other experienced major winners now on the LIV Tour, Brooks Koepka and Jon Rahm, are a further shot back at one over.
