The majority of the 156-man field struggled to adapt to the firm and fast course on the opening day as only 17 players managed to break 70, with Kisner taking full advantage of the benign early conditions to fire a five-under 66 which proved enough for the outright lead at the close of play.
Erik Van Rooyen and Tony Finau shared second, while McIlroy felt he validated his decision to be more aggressive as he carded a three-birdie 69 along with the likes of Jon Rahm, Justin Thomas, Danny Willett and 2015 champion Zach Johnson.
Tiger Woods birdied two of the first four holes but could not avoid errors on the back nine as he settled for a level-par 71, while defending champion Jordan Spieth was left to rue a poor finish in a 72 in which he dropped four shots over the closing four holes.
Kisner will sleep on the outright lead in a major for the first time in his career after staging a superb recovery from a bogey at the fifth, hitting straight back with a huge putt for eagle on the next green before a birdie at the eighth took him to the turn in 34.
The American, who is sharing a house nearby with a number of major winners including Spieth, Thomas and Johnson, raced to the top of the leaderboard with three consecutive birdies from the 13th and parred safely in to stay at five under par.
“I think I only hit four drivers all day, maybe five,” said Kisner, who required only 22 putts on day one. “I just want the ball on the fairway because it’s not an overly-long golf course. You’re not going to have that many long clubs into the hole.
“If I can keep it in the fairway, I feel like I can control my golf ball around the green. The greens are calm, and around the greens are flat. I feel like any time I’m around the green I’m going to make par at the worst. So that’s been my gameplan.”
Van Rooyen, who held the 54-hole lead at the Irish Open a fortnight ago, also got to five under before dropping his only shot of the round at the final hole, while Finau made a rare three at the 18th – his eighth birdie of the day – to join the South African in a share of second.
Last week’s Scottish Open champion, Brandon Stone, continued where he left off at Gullane as he fired a confident 68 along with American duo Ryan Moore and Brendan Steele, with McIlroy among 10 players on two under par.
The 2014 champion took the opposite approach to Kisner and whipped the cover off his driver several times, and the policy paid off as he made three birdies against just one early bogey at the fifth.
Willett declared he was “enjoying golf again” after his 69 in the third group out, although the former Masters champion left Carnoustie a little frustrated having bogeyed the final two holes to take some gloss off his five-birdie card.
Rickie Fowler, who is also staying in the star-studded house with Kisner and co, returned a “fun” 70 to match the scores of 2016 winner Henrik Stenson, fellow Swede Alex Noren and in-form Italian Francesco Molinari.
Woods failed to build on his bright start, making his first bogey at the 10th before responding with another birdie at 11, but he would make further mistakes at 13 and 15 before doing well to scramble pars down the stretch to stay within five strokes of the lead.
Spieth was nicely placed on three under until he double-bogeyed the 15th and blotted his card again at 16 and 18 to slip to one over alongside playing-partner and world No 3 Justin Rose, who made an ugly seven at the long 14th but finished on a high note with a birdie at 18.
US Open champion Brooks Koepka produced the fightback of the day, slipping to five over at the turn after dropping six shots in a dreadful five-hole stretch before he began the inward nine with four birdies in five holes.
Koepka closed on one over, but his close friend and world No 1 Dustin Johnson has his work cut out to avoid an early exit after he stumbled to a 76 which he capped with a triple-bogey seven at the last hole.