(CNN) -- On paper Novak Djokovic and Andy Murray might be the favorites to reach the U.S. Open final since they were the last men standing in three of the four previous majors.
But neither will enter the season's final grand slam in good form after they exited in the quarterfinals of the Cincinnati Masters on Friday.
World No. 1 Djokovic was the first to go, falling to big-serving John Isner 7-6 3-6 7-5 and Murray was soon joining him in the locker room. The world No. 2 was ousted by Tomas Berdych 6-3 6-4.
Djokovic hasn't won a title since April and lost in heartbreaking fashion to Rafael Nadal in the semifinals of the Rogers Cup in Montreal last week.
Murray, meanwhile, might still be coming to terms with his epic victory at Wimbledon that ended Britain's 77-year men's singles drought, although Berdych improved to 6-4 against the Scot.
"It's disappointing that I played this way," Djokovic told reporters. "For me it's very disappointing.
''I just played a very bad match overall. Terrible match. From beginning to end, except the start of the second set, I was just a different player totally.''
Djokovic opened the door for Isner in the tiebreak when he double faulted at 3-3. He saved four break points to start the second and looked to be in control but buckled as he served to stay in the match at 5-6 in the third.
He'll have to wait to complete his Masters collection.
It was the 22nd-ranked Isner's second win over Djokovic, both on home soil.
"I really feel like the crowd in both matches really, really helped me out," Isner told the ATP's website. "It was just so much fun to play out there."
Murray, the defending U.S. Open champion, lost to the unpredictable Ernests Gulbis in the third round in Montreal. He didn't break Berdych, missing a break point in the first set and three in the second.
Juan Martin del Potro, the 2009 U.S. Open winner, advanced to the semifinals with a three-set win over resurgent Russian Dmitry Tursunov.
Nadal, riding a 12-match winning streak on hard courts, will face Roger Federer in Friday's marquee encounter.
In the women's draw, top-seed Serena Williams eased past Romania's Simona Halep 6-0 6-4 and former world No. 1 Jelena Jankovic progressed by defeating Roberta Vinci by the same score.