Isner led 4-1 in the first set before losing his momentum after a rain delay of 1 hour, 4 minutes and recovering to beat Sock 7-6 (7), 6-4.
"I came out flat after the rain delay," Isner said. "Had it not rained I could have won the first set a little more easily. That took a little out of me."
Isner will play Andy Roddick on Saturday in a matchup of top Americans headed to the London Olympics after the tournament. Roddick, the No. 4 seed, beat Michael Russell 6-3, 6-4 earlier Friday.
Go Soeda upset Olympics doubles partner Kei Nishikori 6-2, 6-1 and will play Gilles Muller of Luxembourg in Saturday's first semifinal. Muller defeated Matthew Ebden of Australia 6-4, 6-4 in Friday's first quarterfinal.
Sock, 19, challenged Isner with his persistent drop shots and devastating forehand winners. But Sock's mistakes, including two double-faults in the tiebreaker, were too much to overcome. Isner finally won the first set on his ninth set point.
The second set was tied 4-4 when Isner broke Sock's serve. The 6-foot-9 Isner then used his big serve to finish the win.
Sock, a wild-card entry, was making his first appearance in an ATP quarterfinal.
Isner is attempting to play in his third straight Atlanta final. He lost to Mardy Fish in the last two finals.
The Soeda-Nishikori match was the first pairing of two players from Japan in an ATP quarterfinal since the Open era began in 1968. Each also will represent Japan in singles in the London Olympics.
Soeda said Friday's draw was difficult for him but perhaps more difficult for Nishikori, Atlanta's No. 3 seed who is ranked 19th in the world. Soeda is ranked No. 54.
"Actually I don't want to beat Kei because we are good friends," Soeda said. "This is tough to have to play. I think he was more nervous. I was nervous, too, but his ranking is high. I have nothing to lose. I think it is easier to win."
Nishikori won only 43 percent of his first serves. He says he is still returning to form from a left oblique injury.
"I was injured before Wimbledon," Nishikori said. "I guess I didn't get my confidence yet."
Nishikori didn't blame the loss on nerves or the fact he was playing against his doubles partner and friend.
"I didn't feel much pressure," Nishikori said. "I just didn't play well, I think.
"I couldn't put in the ball, especially my backhand and my serve."
The match was the first between the friends in an ATP event.
Nishikori said Soeda "played unbelievably good."
"He didn't miss and he was really aggressive," Nishikori said. "At the same time I didn't play well. I couldn't put in the ball somehow. I lose my confidence."
Russell, 34, was the oldest player in the field.
Roddick broke Russell's serve to go up 5-3 in the first set. The second set was even at 4-4 when Roddick broke Russell's serve again.
Those were the only two breaks of the match.
Roddick won 86 percent of his first serves and faced only one break point. He had 12 aces.
"If I could take the serving stats from today and apply them to any match, I would sign up right now," Roddick said. – Sapa-AP