Djokovic hardly raised a sweat in the Californian desert as he eased to a 6-1 6-3 victory over Frenchman Julien Benneteau, before the towering Isner rode his booming serve to a 7-6(4) 7-6(3) win over Latvia's Ernests Gulbis.
Djokovic was not at his absolute best but was never in any real danger against the 32-year-old Benneteau, who beat him at Indian Wells eight years ago when the Serb was still a teenager.
Djokovic, 26, raced through the opening set in less than half an hour with two service breaks and four aces despite the windy conditions and an approaching sand storm.
The first six games of the second set all went with serve before Djokovic reeled off the last three in a row to seal a comfortable victory in less than 70 minutes.
He broke Benneteau for a 4-3 lead when the Frenchman double faulted, then again to wrap up the win when his opponent hit a forehand long and wide.
"I felt like I was very focused on the court from the start, and it's what I was looking for. It's never too easy," said Djokovic, who won the Indian Wells title in 2008 and 2011.
"First few matches I played good tennis but I had some ups and downs. Today was very stable from the first to the last point.
"He made a lot of unforced errors, and obviously I just needed to make him play an extra shot and serve well. I have done everything I wanted."
Isner had a tougher time against Gulbis, saving a set point before winning the opener in a tiebreaker after the first 12 games went with serve.
Isner fell behind in the second set when Gulbis found a way to break his serve, for just the second time in the tournament, but the Latvian was unable to capitalize as the American broke back and won the second tiebreaker.
Djokovic was beaten by Isner in the semi-finals at Indian Wells two years ago, losing first and third-set tiebreakers.
"He's definitely not somebody you like to play in the big heat with such serve," Djokovic said.
"It's very challenging because he doesn't miss his serve too much, so you have to kind of be able to hold your composure from the first to the last point and be ready to play three tie-breaks."
Djokovic will go into the semis as a heavy favorite but Isner will not be without his supporters.
"Two years ago I took the court believing I could win that match, so it's much of the same here in 2014," said Isner.
"But, I think I can draw a little bit from that in 2012. It's a good situation for me. I'd like to have the crowd on my side like I did two years ago.
"All that it helps me so much. It's an advantage for me I think to play here at home. But at the same time, it's going to be very tough."
Saturday's other semi-final will be between Switzerland's Roger Federer and Alexandr Dolgopolov of Ukraine, who won their quarter-finals on Thursday.
(Reporting by Julian Linden in New York, editing by Peter Rutherford)