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Murray, a three-time semi-finalist in Paris, will face either Japan’s Kei Nishikori or Richard Gasquet, the last French player standing, in the last-eight.
It will be 29-year-old Murray’s 20th appearance in the quarter-finals of the last 21 majors after braving an Isner storm in the first set where he faced down three set points in the tie-breaker.
“It was a very important tie-break to win. I got lucky on his first set point when I guessed right on a short forehand,” said Murray.
Isner was bidding to become the first American man in the last-eight in Paris since Andre Agassi in 2003.
Having not allowed Murray a single break point, the 31-year-old squandered three set points in the breaker before the British star pounced to pocket the opener.
Rain forced the pair off Suzanne Lenglen court for an hour with Murray 2-1 ahead in the second set before Isner was broken for the first time in the 10th game which allowed the world number two to take the set.
Murray broke for 3-1 in the third before Isner just clung on saving two more break points in the sixth game.
The world number two wrapped up victory — and his sixth win in six clashes with the big American — with his ninth ace of the tie.
Isner, meanwhile, was undone by Murray’s superior returning which contributed to his 57 unforced errors.