"It all comes at a great time for me. It was something I was wishing to be more aggressive as the tournament progresses and to be able to stay committed to play every point, to win every point, regardless of the score.''
Murray had a poor first-set tiebreak losing the last four points after having led 5-3 but reasserted his command over Istomin with a break in the first game of the second and swept to victory.
Next up for Djokovic is Youzhny, who was two points from defeat but came back to edge two-time major champion Lleyton Hewitt 6-3, 3-6, 6-7 (3), 6-4, 7-5.
Hewitt, the former world No.1, looked like booking his first grand slam quarterfinal berth in four years after a wretched run of injuries.
The Australian was within two points of winning at 5-2 in the last and served for the match at 5-3.
"It's one of the hardest games to win the last one,'' Hewitt said.
While Youzhny and Hewitt slugged out a grueling five-setter, Djokovic needed only 79 minutes to beat Granollers, and had embarrassingly large advantages over the last two sets in points won (50-15) and winners (22-3), and he even won on 21 of 22 moves up to net, which isn't his normal style.
"It's all coming together for me right now,'' Djokovic said. ``I'm aware of the fact that as the tournament goes on I'm going to have bigger challenges, better quality players, higher ranked players, but I'm ready for that challenge. I look forward to it.''
While Djokovic will be a pronounced favorite against Youzhny, Murray will be at slightly longer odds against Wawrinka, who beat Tomas Berdych 3-6, 6-1, 7-6 (6), 6-2.
The key moment came when Wawrinka served a big ace down the middle to seal a tight third-set tiebreaker, and he was untroubled in the fourth to close out.
Murray leads the head-to-head series against the Swiss 8-5, but they've split their two previous meetings on the U.S. Open's hard courts: Murray won in 2008, and Wawrinka won two years later. Wawrinka also won their only match this season, 6-1, 6-2 on red clay at Monte Carlo in April.
"He's very tough. Very talented,'' Murray said. ``We played once on this court when we were much younger. But a lot has changed since then.''
In the women's draw, top seed Serena Williams trounced Carla Suarez Navarro 6-0, 6-0 the first `double-bagel' in a U.S. Open quarterfinals since Martina Navratilova did it in 1989.
"I played really good,'' Williams said. ``I was just more focused than anything. I like to believe there is room for improvement.''
Williams' semifinal opponent will be fifth-seeded Li Na, who needed nearly 2 hours to get past 24th-seeded Ekaterina Makarova of Russia 6-4, 6-7 (5), 6-2.
Li has only won one of nine career matches against Williams.
"Tough, tough opponent,'' Li said. ``But is (a) good challenge to play against her.''
The quarterfinals on the other half of the draw are Wednesday: second-seeded Victoria Azarenka of Belarus against the experienced Daniela Hantuchova of Slovakia, and 10th-seeded Roberta Vinci against Flavia Pennetta in a matchup between two Italians in their 30s.
While the other women in that section all advanced Monday, Azarenka's fourth-round match against 2008 French Open champion Ana Ivanovic was postponed until Tuesday because of rain. Azarenka got off to a slow start, but eventually got going and beat the 13th-seeded Ivanovic 4-6, 6-3, 6-4 in a topsy-turvy match with a combined 16 service breaks and 17 double-faults.
-AP