The 22-year-old Scot rated Isner's serve among the best in the game, so he was delighted to wear down the American after a crucial service break in the eighth game of the second set. He fended off break points in the next game to serve out the set.
"It's tough. I had my coach serving at me from the service line this morning to try to get used to it," Murray said of the 6-foot-9 Isner's serve. "But once you get out there it's kind of tricky."
Murray broke serve again in the seventh game of the third set when the American netted a forehand and then smashed his racket into the court in disgust.
"It's been good. I moved really well since the start of the tournament," Murray said. "I didn't drop a set yet ... not too much to complain about."
Fifth-seeded Murray faces a daunting quarterfinal as he attempts to win his first major title. Nadal was scheduled to play Croatia's Ivo Karlovic in the following match at Rod Laver Arena _ the winner meeting Murray in the next round.
The loss was Isner's first of the year, which started with his first career ATP title.
Zheng Jie set another national mark by becoming the first Chinese player to reach the Australian Open quarterfinals when she beat Alona Bondarenko 7-6 (6), 6-4.
The 26-year-old Zheng had already matched her own previous best run at Melbourne Park by reaching the fourth round, but is still a win away from equaling her best performance at a Grand Slam tournament.
She made a stunning charge to the Wimbledon semifinals in 2008, becoming only the second wild-card entry to reach the semis at a major and ousting then No. 1-ranked Ana Ivanovic along the way.
No. 31-seeded Bondarenka had been on an eight-match winning streak after a title run at Hobart last week, which included a quarterfinal win over Zheng.
Zheng was more steadfast in the tiebreaker after the pair traded three service breaks in the opening set.
Bondarenka held for a 4-3 lead in the second, but Zheng won the last three games after holding a lengthy service game to level it and breaking the Ukraine player at love in the next.
Zheng earned match point with an angled volley and Bondarenko slammed her racket into the court. She put a backhand out next point to give Zheng the win.
It was Zheng's first straight sets win this week in Melbourne, where she and No. 16 Li Na set a mark as the first two Chinese woman to reach the fourth round at the same major.
Top-ranked Roger Federer and Australian hope Lleyton Hewitt both won Saturday to set up a meeting in the fourth round. The winner of that could meet Nikolay Davydenko in the quarterfinals. Sixth-seeded Davydenko is on hot 12-match winning streak, including wins over Federer and No. 2 Rafael Nadal. But he'll have to get past 2009 semifinalist Fernando Verdasco to get a shot at Federer or Hewitt.
Hewitt had to play only 12 games in 54 minutes to advance over Marcos Baghdatis, the 2006 finalist, who retired with a right shoulder injury after falling behind 6-0, 4-2.
Their last meeting at Melbourne Park was two years ago and significantly more dramatic. Hewitt finally won at 4:34 a.m.
Federer ousted No. 1 Albert Montanes 6-3, 6-4, 6-4. He's reached the semifinals or better at the last five Australian Opens, winning three of his record 15 Grand Slam titles in Melbourne, and is on a 14-match winning streak against Hewitt.
Novak Djokovic, who is ranked No. 3 and beat Federer in the semifinals en route to the 2008 title, defeated Denis Istomin 6-1, 6-1, 6-2 and next plays Poland's Lukasz Kubot. Kubot, who finished last year ranked No. 101, got a walkover when No. 20 Mikhail Youzhny withdrew with a wrist injury.
Sixth-seeded Davydenko beat Argentina's Juan Monaco 6-0, 6-3, 6-4 to set up the fourth-rounder against Verdasco, who advanced when Stefan Koubek retired because of a virus after losing the opening set 6-1.
Davydenko hasn't reached the final of a major and never gone past the quarterfinals in Australia, but is on the hottest streak.
And although he doesn't have a high public profile, he certainly hasn't been sneaking up on players due to his titles at last year's season-ending championships in London and the season-opening tournament in Doha.
Jo-Wilfried Tsonga, the 2008 runner-up, beat Tommy Haas to advance 6-4, 3-6, 6-1, 7-5. Next for him is Nicolas Almagro of Spain, who beat Colombia's Alejandro Falla 6-4, 6-3, 6-4.
The Williams sisters moved a step closer to a semifinal meeting, with defending champion Serena beating No. 32 Carla Suarez Navarro 6-0, 6-3 and Venus advancing 6-1, 7-6 (4) over Australian wild-card entry Casey Dellacqua.
U.S. Open runner-up Caroline Wozniacki downed Israeli Shahar Peer 6-4, 6-0 to set up a fourth-round against China's Li, who advanced 7-5, 3-6, 6-2 over 2008 semifinalist Daniela Hantuchova.
Men's U.S. Open champion Juan Martin del Potro was in action later Sunday against No. 14 Marin Cilic, while No. 7 Andy Roddick faced No. 11 Fernando Gonzalez of Chile.