The top-ranked Serb brushed off the 6ft 10ins (2.08m) Isner to clock up his 27th straight victory at a tournament where he has never been beaten and has now won 23 sets in a row.
The lop-sided defeat was almost embarrassing for the 13th-ranked Isner, clocking in a shade quicker than Djokovic’s similar straight-sets humiliation of China’s 219th-ranked Zhang Ze in the previous round.
Djokovic finished off Isner with a service winner on his first match point to move past Jimmy Connors and into sole second place for best unbeaten starts at a tournament, behind Nadal’s 31 at the French Open.
Next up for the seemingly unstoppable Serb, who won three out of four Grand Slam finals this year to reach 10 major titles, is Spain’s David Ferrer, who beat Taiwanese wildcard Lu Yen-hsun 6-3, 6-1.
Earlier, life was a little trickier for Rafael Nadal as he was forced to come from a set down against America’s Jack Sock before setting up a chance for revenge in the semi-finals against Fabio Fognini.
The out-of-sorts Spanish great, scrapping to recover his form after a tough year, was outgunned by Sock’s howitzer forehand but he dug deep to see off the world number 30, 3-6, 6-4, 6-3.
“Yes, it was an important victory for me. Obviously I finished the match playing better than what I started. It’s important because I came back,” Nadal said.
“This year I lost a lot of matches when I had an advantage. So to have the chance to win a match when I start losing this one, so it’s important for me, too.”
Nadal, into his first hardcourt semi-final for more than a year, will now face Fognini, who has beaten him three times this season including in last month’s US Open third round.
“He’s a great player. When you play against a great player, especially if you don’t play to your best, your chances are lower,” Nadal said of the Italian, who beat Uruguay’s Pablo Cuevas 6-1, 2-6, 6-2.
“If I am able to play my best tomorrow… I am going to have my chances. If not, it’s going to be tough. It’s simple. Sport is simple.”
In the women’s draw, Ana Ivanovic beat Anastasia Pavlyuchenkova 6-3, 7-5 to set up a semi-final with Timea Bacsinszky, who recovered from a first-set ‘bagel’ to beat Sara Errani 0-6, 6-3, 7-5.
Agnieszka Radwanska beat Angelique Kerber 6-1, 6-4 to go into a semi-final clash with the in-form Garbine Muguruza, who halted the run of American qualifier Bethanie Mattek-Sands 6-1, 7-5.