Isner beat Marinko Matosevic 7-6 (8), 6-4 in hot conditions, taking advantage of the Australian's mistakes to run his Atlanta record to 14-3.
Sock later topped Slovakia's Lukas Lacko, 7-6 (6), 6-2 after trailing 3-5 in the first set.
Matosevic and Isner both slowed their pace of play in the second set as temperatures were in the high-80s under a blazing sun. On several occasions, Isner bent over between points to gather himself.
"I knew he was struggling out there a little bit, and he knew I was struggling a little bit," Isner said after ending the mid-afternoon match with his 17th ace. "A lot of times in situations like that ... even though I appear to be super tired and I am super tired, I can muster up enough energy to pop some big serves in.
"The beginning of that second set it felt like someone put us both in an oven."
In the first game, Matosevic broke Isner's serve. The defending champion would go on to win a modest 70 percent of his service games, well below the ATP-leading 93 percent win rate that he carried into the quarterfinals.
Matosevic's errors made up for gaps in Isner's serves. The Australian sent an overhand smash well long to enable Isner to break serve for a 4-3 lead in the first set, and Matosevic double faulted to hand Isner set point in the 10-8 tiebreaker.
Back-to-back double faults gave Isner a 4-3 lead in the second set.
"It was just as hot as the 43 Celsius day I played in Australia this year if not hotter," Matosevic said. "(Isner) amped it up, and started serving like 10 mph faster in the second ... it was really, really hot out there."
The 21-year-old Sock advanced to his second career semifinal. He made his first two weeks ago by beating Isner in straight sets on grass at Newport.
In May, Isner beat Sock in straight sets on clay in Nice, France.
They won't need scouting reports.
"We practice together almost every day now out at Saddlebrook in Tampa, and so I'm going to have to go out and use what I know from practice," Sock said. "These (hard) courts suit him pretty well because it's high bouncing and when a 7-foot guy is serving down on you it's not going to be easy."
Sock teamed with Pospisil three weeks ago to win the men's doubles title at Wimbledon, and the pair will played a doubles match Saturday against Becker and his fellow German Frank Moser before singles play begins later in the afternoon.