Third-ranked Koepka, in prime position for his fourth major title, fired a level-par 70 at Bethpage Black to stand on 12-under 198 entering Sunday's final round.
"I feel confident. I feel good. I feel excited," Koepka said. "It's nice to have a seven-shot cushion. Just hit the center of the greens and try to par this place to death.
"(I'll) just stick to my routine, do what I'm doing. I'm not thinking of seven-shot lead, winning the tournament. I'm thinking of what I need to do on the first shot first tee."
The 29-year-old American owned a record edge over a pack on 205 that included top-ranked Dustin Johnson, fellow Americans Harold Varner and Luke List and Thailand's Jazz Janewattananond.
"It's going to take something special to catch Brooks," Johnson said. "But it's definitely do-able on this course."
The best final-round comeback by a PGA winner was seven strokes by John Mahaffey in 1978.
"We're all pretty much playing for second," List said.
Matt Wallace, trying to become the first Englishman to win the PGA since Jim Barnes in 1919, shot 70 to share sixth on 206 with Japan's Hideki Matsuyama.
No one in major golf history fired a lower 36-hole score than Koepka's 12-under 128, and his seven-stroke advantage was the second-largest major halfway lead, trailing only Henry Cotton's nine-shot edge in the 1934 British Open.
If Koepka does capture the Wanamaker Trophy and the $1.98 million (1.77 million euros) top prize, he will be the first man to own back-to-back titles at two majors simultaneously. Koepka seeks a third consecutive US Open crown next month at Pebble Beach.
"He's definitely, in these events, playing on a different level than most anyone else," four-time major winner Rory McIlroy said of Koepka. "It's awesome. It's so good. It's great to watch."
- Koepka grinds well -
Koepka's routine tee blast and wedge approach made him a threat when he found the fairway. He missed a six-foot birdie putt at the first but sank a five-footer at the second and a three-footer at the fifth to reach 14-under and lead by eight.
From there, Koepka grinded through troubles with success to sustain his huge lead.
Koepka found tall weeds and greenside rough at the seventh but rescued par by sinking a nine-foot putt and saved par again after missing the green at the par-3 eighth.
Then came Koepka's worst slip of the week, a botched tap-in to bogey nine and a missed fairway to bogey at 10.
Koepka went into trees and dense rough at the par-5 13th but responded by blasting out to 16 feet and curled in a birdie putt but made a final bogey at 16.
"I left a bunch of putts short," Koepka said. "I'm pleased I'm stroking it well. Just need to hit them a little harder."
The PGA's largest prior 54-hole lead was five strokes, last achieved by Ray Floyd in 1982. The low 54-hole tournament score remains 196 by David Toms in 2001.
Koepka owns the PGA 18-, 36- and 72-hole scoring records.
American Jordan Spieth, seeking a win to complete a career Grand Slam, and Australian Adam Scott, seeking a second major title after winning the 2013 Masters, were Koepka's nearest rivals when the day began but both fired 72 Saturday to stand on 207.
- Smooth Jazz plays well -
Jazz, ranked 72nd, closed with a 10-foot birdie putt to shoot 67. Jazz sizzled early with three birdies in the first six holes and curled in a tricky 13-footer for birdie at 10 as well.
The 23-year-old from Bangkok, playing in his first PGA Championship, took bogeys at the par-3 14th and 17th before answering at 18.
Varner, ranked 174th, birdied the par-5 fourth and 13th holes and closed with a five-foot birdie putt to shoot 67 and take his best position in a major.
"It's so hard," Varner said. "You've got to just take your time and execute your shots."
Unheralded 76th-ranked List, winless in five US PGA Tour seasons, reeled off three birdies in a row starting at the 12th hole, getting within five of Koepka, but closed with back-to-back bogeys to fall back.
"The wind started blowing the whole back nine," List said. "It really showed its teeth."
Johnson, who shot 69, is trying to keep Koepka from overtaking him atop the rankings as well as seeking a second major title after the 2016 US Open.
"It was one of those days when I didn't score that well but I hit a lot of good shots," Johnson said.