Isner, a former Georgia standout, will face seventh-seeded Lleyton Hewitt, who overcame a disastrous start to beat third seed Ivan Dodig 1-6, 6-3, 6-0.
In the night quarterfinals, Ryan Harrison beat Santiago Giraldo 6-3, 3-6, 7-6 (2), and second-seeded Kevin Anderson faced Denis Istomin.
The match between Blake and Isner was close in many statistical categories, but Isner extended his ATP Tour-leading tiebreaker record to 23-6 this season. Blake sank to 0-4.
“A lot of times, I play my best tennis in the tiebreak,” said Isner, who also won a tiebreaker Thursday in a 7-6 (9), 4-6, 7-5 victory over Christian Harrison. “It’s not just coincidence. I’m more aggressive. I need to have more urgency in the rest of the set.”
Isner fell behind 0-3 in the second set, threw his cap to the court, kicked it, and then a couple games later went back on serve when Blake double-faulted on a break point to see his lead shrink to 4-3.
Hewitt didn’t throw anything earlier, but he turned his match around abruptly to beat Dodig, ranked 36th in the world. Dodig needed just 17 minutes to wrap up the first set, in which he served eight aces and Hewitt won but two points against first serve.
Gradually, Hewitt began timing serves and when Dodig sent a forehand into the net 40 minutes later, Hewitt had broken for a 5-3 lead.
He rolled from there. The former world No. 1 broke serve all three times in the third, when Dodig won just 42 percent of all points on his own first serve and on a mere 1 of 9 second serves.
“I couldn’t get into the match,” Hewitt said. “He served fantastic. For a set and a half, I don’t think he could play any better. I thought if I could keep it close, he might get tired.”
Isner has made his way to the Atlanta semis for the fourth time in as many tries. He owes much of that to a big first serve – reaching into the mid-140 mph range several times – and a second he spins hard.
Isner had 21 aces to Blake’s seven.
“Just having the weapons he has on his serve ... it doesn’t give you any rhythm (as a returner),” Blake said. “(His second) can be just as effective as most guys’ first serves.”
The players stayed on serve in the tiebreaker through 11 points. When Blake served against 5-6, he got it in but after a couple volleys, sent a forehead wide left to end it.
“When I’m in that situation, it sort of favors me given how I can end the points quickly,” Isner said. “In the tiebreaker if I’m able to get up 1-0 out of the gate, or winning two points on my serve (to go up 2-1), it really puts a lot of pressure on them. If they just slip up on one serve I can . . . try to play aggressively for the most part.”