The 6-foot-11-inch Opelka used his height and power to fire down 17 aces, though the 20-year-old was not really happy with his biggest weapon.
"I didn’t serve as well as I’d have liked to or as well as I usually do," the world number 228 said after the biggest win of his career.
"I was really pleased with how I played from the baseline though. I thought I hit my forehand great and made it really tough for him to be offensive, which is his game."
World number eight Sock spoke of the difficulty of playing against someone of Opelka's height.
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"You’re not really ever in control against a seven-foot guy who can serve you off the court," he said.
"Even after winning the first set it’s still 50-50 with his style of play."
Isner came out on the wrong end of three consecutive tiebreaks against German Peter Gojowczyk, who prevailed 7-6(3) 6-7(4) 7-6(5).
Thirty aces were not enough for Isner in a match that did not feature a service break.
Raonic was beaten more comprehensively, outplayed 6-2 6-4 by American Steve Johnson, who earned his first ever victory over the Canadian.
Raonic was nonplussed by his own performance.
"I’ve got to definitely review it, think about it, because that was a pretty poor level I put out there today," he said.
"Not much to be happy with. I had a tough time with a lot of things today."
(Reporting by Andrew Both in Adelaide, South Australia; editing by Amlan CHakraborty)
