Djokovic has struggled in the past with the 6-foot-10 (2.08m) Isner’s bombing serve on the hardcourts of the California desert.
But the reigning Australian Open champ got the best of his opponent in the key tiebreaker.
“John has one of the best serves in the game,” Djokovic said. “It was difficult to hang in there mentally.
“He had chances in the second set but I managed to get through in straight sets.”
Djokovic booked a quarter-final clash with 35th-ranked Bernard Tomic of Australia.
Tomic eliminated fellow Aussie Thanasi Kokkinakis 6-4, 4-6, 6-4.
In 2012, Isner upset Djokovic 7-6 (9/7), 3-6, 7-6 (7/5) in the semis, a defeat Djokovic avenged last year by beating Isner 7-5, 6-7 (2/7), 6-1 to reach the final.
Djokovic now has a 6-2 advantage in career meetings, with nine of the sets going into tiebreakers. Isner has won six of those, so Djokovic felt fortunate to squeak through this time.
“With his size and his serve he can beat anyone so I am very pleased with the victory which for me is very big,” Djokovic said.
Djokovic hammered seven aces and saved both break points he faced in the one hour, 31 minute match.
Four-time Indian Wells winner Roger Federer needed just 69 minutes to oust American Jack Sock 6-3, 6-2.
“The first set was really good tennis,” Federer said. “I played well throughout and was able to serve better than Jack today.”
In the quarter-finals, the Swiss second seed will face ninth-seeded Czech Tomas Berdych, a 6-2, 4-6, 6-4 winner over compatriot Lukas Rosol.
“The opponents are getting tougher as you get into the back end of the tournament,” Federer said.
Federer and Berdych have met 18 times with the Swiss holding a 12-6 lead.
World number three Rafael Nadal rolled over France’s Gilles Simon 6-2, 6-4.
The left-handed Spaniard hammered four aces and broke Simon five times to set up a meeting with hard-hitting Milos Raonic of Canada.
“I played a solid match against a tough opponent who has good tactics,” Nadal said. “I only had two bad games with my serve.”
Raonic hammered a 241 kmph (150 mph) serve en route to a 6-3, 6-2 straight set win over Tommy Robredo of Spain.
– Tough task for Raonic –
Raonic is in his second straight quarter-final but he will have his work cut out for him because he has never beaten Nadal in five career meetings.
Raonic said Nadal can be an intimidating figure to play against.
“Rafa really puts it out there to be noticed by his opponents and to bring himself up, as well,” Raonic said.
“The last time I played him, I managed to do a better job than the previous few times, so I think I have a reference base.”
Fourth seeded Andy Murray, trying to rebound from a subpar 2014, defeated Adrian Mannarino 6-3, 6-3 in the fourth round.
“It was a tricky match,” said the 27-year-old Scot. “He’s played well this year, had a few good tournaments.
“He’s a tough guy to play against. Very unorthodox style. He has a very, very good backhand cross court. Hits it very low over the net, very flat,” added Murray, whose 496th career match win equalled Tim Henman’s mark for the most in the Open Era by a British man.
Murray next faces Spain’s Feliciano Lopez who upset fifth seed Kei Nishikori of Japan 6-4, 7-6 (7/2).