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Murray, who could face defending champion Rafael Nadal next, is the first Briton into the last eight here since John Lloyd in 1985.
The young Scot showcased his exciting strokeplay against the big-serving American and has yet to drop a set in his four victories at the year’s opening Grand Slam.
Murray, the 2008 US Open finalist, has now given himself a chance to have a crack at Nadal in the quarters, with the Spanish second seed taking on unseeded Croat Ivo Karlovic later Sunday.
“I’ve been moving pretty well and I played some great shots out there, so I haven’t got much to complain about so far,” Murray said.
He neutralised the 6ft 9in (2.06 metre) tall Isner’s serve, which he rated one of the best in men’s tennis.
“He has one of the best serves and I had my coach serving at me from the service line this morning just to get used to his height, but once you get out there it’s still tricky,” Murray said.
“The first set was the key because he is a little bit tired after he won the Auckland tournament last week and he’s had some long matches and he’s winning doubles here as well.”
It was Murray’s greater variety of strokes, including drop shots and volleys to the feet of Isner, which proved decisive.
Murray earned three service breaks and only conceded four break points in not dropping his serve in the two hour 12 minute contest on Rod Laver Arena.
While the imposing Isner, 8-2 this season, produced the greater number of winners (43), Murray’s was immaculate and only made eight unforced errors in the 30 games.
Isner, who was bidding to reach the quarter-finals of a Grand Slam for the first time, finished the tournament with 95 aces.
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