It means that the home winless streak will stretch to six years, making it the worst for American men since the Open era started with a win for Arthur Ashe in 1968.
Top seed and defending champion Roger Federer, meanwhile, moved a step closer to a record-equalling sixth straight title with a routine 7-5, 6-2, 6-2 win over outclassed Tommy Robredo of Spain.
In the last eight, he will play the man be beat in Paris to end his French Open jinx, Robin Soderling, who moved on when Nikolay Davydenko abandoned with a thigh strain when trailing 7-5, 3-6, 6-2.
Verdasco will go up against fourth seed Novak Djokovic of Serbia who eased past Radek Stepanek of the Czech Republic 6-1, 6-3, 6-3 in a disappointing night-time session match on the Arthur Ashe Stadium court.
Isner, at 6 foot 9 inches (2.03m) the second-tallest player in world tennis, in the previous round had ended the hopes of Andy Roddick, who had been regarded as the best American hope of ending a home winless drought dating back to 2003. Roddick himself was the winner on that occasion
But Isner found in Verdasco a very different prospect with the match an exercise in contrasts between the towering American who relies on his big serve and staccato rallies and the tough Spaniard, more accustomed to grinding it out from the baseline.
Isner grabbed a one set lead with two breaks to one, but he was gradually worn down by the relentless pressure applied by Verdasco and when his serve started to waiver midway through the third set there could only be one winner.
Federer edged a tight first set against Robredo and turned on the turbo to race away for a comprehensive win in 1 hour 48 minutes.
The Spaniard, losing for a ninth straight time to the world No.1 in seven years, admitted he had been helpless to halt the assault. "When he saw that he was a set up, he started hitting it harder. Then the match goes easy for him," he said. "Maybe it´s too easy for him, the tennis, so he can even laugh."
The 28-year-old Swiss star is bidding to become the first player since American Bill Tilden in 1925 to win six straight US Open crowns.
He also would make it three out of four Grand Slam titles this year, and for the fourth time in his career, and take his career haul to 16, two clear of second-best Pete Sampras.
Turning to his last eight clash with Soderling, Federer said he expected a tough test even though he had won all 11 previous matches between the two.
Teen titans Oudin, Wozniacki make final eight
Meanwhile, in woman´s section, powerhouse teen phenomenons Melanie Oudin and Caroline Wozniacki rallied Monday to complete an ouster of Russian stars from the US Open and advance to their first Grand Slam quarter-finals.
The unseeded Oudin, who turns 18 on September 23, ousted 13th seed Nadia Petrova 1-6, 7-6 (7/2), 6-3. It was her third triumph in a row after losing the first set to a seeded Russian rival.
Danish ninth seed Wozniacki blasted sixth seed Svetlana Kuznetsova 2-6, 7-6 (7/5), 7-6 (7/3), never trailing in either tie-breaker and keeping the pressure upon the 2004 US Open champion all night.
The reigning French Open champion fired 59 winners but lost by making 63 unforced errors, 31 more than Wozniacki.
The other quarter-final Wednesday will also feature Slam quarter-final debutantes as Ukraine´s 52nd-ranked Kateryna Bondarenko, who beat Argentina´s Gisela Dulko 6-0, 6-0, faces 50th-rated Yanina Wickmayer, a 19-year-old Belgian that Bondarenko beat for her only WTA title in last year´s Birmingham final.
But the focus will be upon Oudin and Wozniacki.
While Oudin cannot speak French despite her Gallic surname, she has shown a mastery of Russian, rallying from first-set losses to eliminate fourth seed Elena Dementieva, former world number one Maria Sharapova and Petrova.
"I know I can compete with the best in the world," Oudin said. "I´m staying in there the whole time. I´m not giving up. Even if I get a set down I believe in myself. I know if I fight as hard as I can that I can do it."
Wozniacki knows she will face a hostile crowd at Arthur Ashe Stadium in support of the home-nation heroine.
"She has had such a great run. She has played some amazing tennis," said Wozniacki. "It´s going to be a tough match but I´m going to give it all I´ve got. Hopefully somebody will cheer for me."
Comeback queen "Oudini" improved to 9-2 this year when losing the first set, and 17-4 in all three-setters, becoming the youngest American in the US Open´s last 16 since Serena Williams a decade ago.
Kuznetsova was the only player to beat US second seed Serena Williams at a Grand Slam event this year, ousting the Australian Open and Wimbledon winner in the quarter-finals.
Kuznetsova took advantage of all three break chances to win the first set in 27 minutes, but blundered in the tie-breaks.
Wozniacki served for the match at 5-3 but was broken, then Kuznetsova saved match points in the 10th and 12th games before again failing in the decider.
"I felt like I was in control of almost all the points," Kuznetsova said. "It´s just the tie-breaks I played bad."
Oudin, ranked 221st a year ago, wears the word "believe" on her yellow and pink shoes at her boyfriend´s suggestion. She made a believer of Petrova despite a rough start, dropping the first set in 31 minutes.
Petrova led 4-3 when Oudin broke to equalize and they served to a tie-break, in which Oudin seized a 5-0 lead and won when Petrova sent a forehand wide.
Petrova rescued six match points in the opening game of the last set but was broken by a defensive lob winner, opening the floodgates. Oudin won on her third match point when her forehand winner finally ended it.
"It was tough. She was all over me. I kept fighting and I got that break and I´m so happy that I won," said Oudin, her voice breaking with joy.
Bondarenko, who saved a match point in her opener against Serbian 11th seed Ana Ivanovic, took revenge for the South American´s second-round ouster of her older sister Alona.
"She kissed me I think five times," Kateryna said of Alona. "I think she is very happy."
Wickmayer advanced 4-6, 6-4, 7-5 over 72nd-ranked Czech teen Petra Kvitova, who ousted Russia´s top-ranked Dinara Safina in the third round.
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