Britain's world number four wasted no time booking his place in the last eight after the previous two days at Flushing Meadows were washed out by rain, wrapping up the victory in just under two hours.
"I was a little bit frustrated in the middle of the second set because I was returning well, hitting the ball well from the back of the court and was giving him chances that I shouldn't have been just because of not serving well enough," said Murray.
The two-day rain delay forced tournament officials to hastily rearrange the schedule, leaving Murray facing the daunting prospect of having to win four matches in four days to win his first Grand Slam title.
"It's not ideal (too play three days in a row) but that's what you have to deal with. You've just got to get on with it," he added.
"You've just got to try and embrace the situation and do all the right things to get yourself ready if you have to play four matches in four days. But I'm still a long way from having to play four matches in four days."
Despite his reputation for holding serve, and the need for three tie-breaks, Isner was broken four times, twice apiece in the first two sets.
But roared on by a partisan New York crowd, he found his rhythm and unleashed 26 aces on his way to victory.
Isner said was expecting a tougher match from Murray.
"I played him in the Australia Open in 2010 and he beat me pretty easily," Isner said. "He would kind of take the air out of the ball and hit a lot of short angles and got me moving.
"I'm going to have to change a couple things up. He's one of the best returners in the game, so I'm going to have to serve my best. When I do get my chances on the return, I will have to take them."
In the men's doubles tournaments Colin Fleming and Ross Hutchings were made to wait for a conclusion to their quarter-final match against fifth-seeded Rohan Bopanna and Aisam-Ul-Haq Qureshi after rain interrupted play.
The match was intriguingly poised in the third set with the British pair 5-6 down, but 30-15 up when organisers decided to postpone the clash late on Thursday with the winners having to play again on Friday.