The 34-year-old, who became a US citizen in January, fired a sizzling six-under-par 66 in relatively calm, sunny conditions at the Kiawah Island Golf Resort to take control of the season's final Major.
Former US Open winner Rory McIlroy, long-hitting American Gary Woodland, Spaniard Gonzalo Fernandez-Castano and Swede Alex Noren charged into contention with 67s while four-times champion Tiger Woods was happy after opening with a six-birdie 69.
Defending champion Keegan Bradley, 1991 winner John Daly and Dutchman Joost Luiten, who briefly led at eight under before bogeying his last four holes, were among a group of eight players who carded 68s at Kiawah, where ocean breezes strengthened later in the day.
Forty-four players broke par on the longest layout to stage a Major championship, making the most of conditions softened by heavy rain earlier in the week. The average score was 73.42.
"I played really good," Pettersson said after breaking 70 for the first time in 21 rounds at the US PGA Championship with an nerveless six-birdie display on a hot and humid day.
"Getting off to a good start was the key to the round. There really wasn't much wind on the front nine, so I knew I had to keep going low because I figured the wind would get up.
"The wind started blowing a little bit on the back nine, and I carried on solid play, hitting a lot of fairways, hitting a lot of greens and making a few putts. It was a great day for me."
Pettersson, who won his fifth US PGA Tour title at the Heritage Classic in April, has missed 10 cuts in the Majors while recording only two top-10 finishes.
"I haven't contended that much in Majors ... but I'd love to have a chance and see what happens," said the Swede, who is bidding to become the 17th different player in a row to claim one of golf's grand slam titles.
"You see different people, and some of your friends, winning Majors, and that motivates you. Long way to go, but I'm thrilled with the start, and we'll see what happens."
McIlroy, who won last year's US Open by a staggering eight shots, sank a 12-footer to birdie his opening hole, the 10th, and picked up further shots at the 14th, 16th, second and sixth to rocket into contention.
"It's a great way to start the tournament," said the 23-year-old Northern Irishman. "Hitting balls on the range this morning, there was completely no wind. It was flat calm and I really thought that I had to take advantage of the conditions.
"Very happy with the round. It's a great score to build on."
Most eyes, though, were on Woods who teed off at the 10th in pursuit of his 15th Major title but his first since the 2008 US Open.
Following an early birdie at the 12th he bogeyed the 13th after finding bunkers off the tee and also with his third shot, and the tricky par-three 14th, where he missed the elevated green to the left off the tee.
However, Woods immediately recovered by sinking a 15-foot birdie putt at the 15th, sparking a cry of "beautiful" from a fan, before rolling in a 25-footer on the 18th green to prompt huge roars from the crowd crammed into the grandstands.
Woods also birdied the first and second, stumbled with a bogey at the fourth, then picked up one more shot at the par-three eighth to finish three strokes off the early lead.
"I'm pleased," Woods said of his start on the 7,676-yard Ocean Course. "I played well today and anything in the sixties is going to be a good start in a Major championship. I'm right there.
"It's one of those days where everyone's going to shoot six, seven, eight under par, but the wind kicked up a little bit and it changed things quite a bit.
"If it had stayed pretty benign, I'm sure you would have had to have shot probably five under par to be in the top 10."
Many of the game's leading players did not fare as well in the opening round, four-times Major winner Phil Mickelson and Masters champion Bubba Watson grinding out 73s in the tougher conditions of the afternoon.
British world number one Luke Donald carded a 74, fourth-ranked Lee Westwood a 75 and US champion Webb Simpson of the US battled to a 79.