Ramey, who missed the cut in his last three PGA Tour starts and is making his Players Championship debut, opened with a bogey-free eight-under-par 64 that left him one shot clear of twice major champion Collin Morikawa (26) at TPC Sawgrass.
Canadian Taylor Pendrith (31) was a further two shots adrift.
Ramey, who won his lone PGA Tour title last year in Punta Cana and is 225th in the world rankings, showed no nerves as he birdied four of his first seven holes and added another four across the back nine to set the early pace.
Morikawa began on the back nine and was cruising along at three under before grabbing a share of the lead with an eagle at the par-five second, his 11th hole, where his approach shot from 235 yards settled three feet from the cup.
Morikawa, who missed the cut last week at Bay Hill, added another two birdies to grab the outright lead in the PGA Tour's flagship event before Ramey overtook him with two late birdies.
"Overall, the game feels really good, and I'm just going to take that into the next few days and just kind of use that momentum to hopefully play three more really good rounds," said Morikawa.
STAR GROUP
While few would be surprised to see Morikawa near the top of the leaderboard many onlookers expected those in the mix to have come from the heavyweight group featuring world number one Rahm, Scottie Scheffler (26) and McIlroy.
The trio, who have traded the top spot in the world rankings this year, were the pre-tournament favourites when they arrived at TPC Sawgrass but experienced mixed fortunes.
Rahm, who has three wins this year, carded his lone bogey on his penultimate hole en route to a one-under-par 71 that left him three back of Scheffler, who birdied three of his final four holes to card a solid 68.
"You don't have a lot of margin to miss out here," said Rahm. "Even when you're in the fairway, you have to hit a lot of quality shots to give yourself a birdie chance."
It was a different story for McIlroy, however, as he began his day with a double-bogey at the par-four 10th where he missed the green with his approach, sent his third shot into a bunker and failed to get up and down.
The four-times major winner, runner-up last week at Bay Hill, responded immediately with a birdie but struggled to find his rhythm and found himself repeatedly playing from the rough on the way to a disappointing 76.
"I feel like this is as penal as I've seen it out of the rough for a long time," said McIlroy. "Yeah, you don't hit it on the fairway here, you're going to struggle."
Last year's champion Cameron Smith (29) is not in the 144-player field, nor are or five of the top-10 finishers from the 2022 Players Championship, as those who joined LIV Golf are banned from competing on the PGA Tour.
