Novak Djokovic defeated Feliciano Lopez 6-1, 3-6, 6-3, 7-6 (7/2) to reach the US Open semi-finals, a 21st last-four spot in his last 22 Grand Slams.
The top seed and 2011 champion, playing in his 26th consecutive quarter-final at the majors, claimed his 55th match win in New York.
Djokovic, this year's Australian Open and Wimbledon champion, also enjoyed his fifth win in five meetings against Lopez and will take a staggering 13-0 career record over defending champion Marin Cilic into their Friday semi-final.
Cilic reached the semi-finals with a 6-4, 6-4, 3-6, 6-7 (3/7), 6-4 win over France's Jo-Wilfried Tsonga.
"Feliciano is one of those rare players who serves and volleys on first and second serves," said 28-year-old Djokovic after winnning a ninth successive quarter-final in New York.
"He has a big serve. I played a bad game in the second game of the second set and it was gone.
"The fourth set was anyone's. He had some break points while I had to wait until the tiebreak to get a look.
"I played it well and I am happy to get through in four."
Djokovic had been pushed to four sets by Lopez's Spanish compatriot Roberto Bautista Agut in the previous round.
But the 33-year-old Lopez, playing in his first US Open quarter-final after 55 consecutive Grand Slam appearances, was shellshocked in the first set.
In front of a subdued Arthur Ashe Stadium which had thinned out after the Serena Williams-Venus Williams blockbuster, Lopez managed just five points on the Djokovic serve in the 25-minute opener and was broken twice.
But Lopez, one of four men over 30 to make the last-eight, rallied in the second set, breaking in the second game on his way to a 4-1 lead.
Djokovic saved one set point but a 10th ace gave serve-and-volleyer Lopez the set 6-3.
The Serb, bidding for a 10th Grand Slam title in New York, took the only break of the third set off a Lopez double fault in the second game.
He then played the perfect tie-breaker in the fourth to take victory while Lopez was left to rue his 48 unforced errors in a match which finished just after 1am on Wednesday.
Over a four-hour battle on Arthur Ashe Stadium, 26-year-old Cilic claimed a fifth win in six matches against Tsonga, firing 29 aces and 63 winners.
But the 30-year-old Tsonga made him work in 35-degree (95 F) heat, saving four match points before the champion went through.
"It was a big mental battle. I lost the fourth set despite having three match points. Jo played some amazing shots," said Cilic, who dashed Tsonga's hopes of completing the set of semi-finals spots at all four majors.
"It was very hot, very demanding. I am proud that I stuck to my game plan and didn't back down."
Tsonga, who had also made the quarter-finals in 2011, went into the tie having not been broken in 56 service games at this year's US Open.
Cilic had to save four break points in the sixth game of the opener.
But it was the Frenchman who cracked first, his perfect serving run ending at 60 as Cilic converted on a fourth break point for a 5-4 lead on his way to securing the opener.
Cilic turned the screw again in the second set, breaking for 3-2 courtesy of a fifth double fault served up by Tsonga.
Tsonga looked doomed when he managed just three points off the first three Cilic service games of the third set, but shook himself out of his lethargy to win three games on the bounce and claim the set.
Tsonga fought off two match points in the 10th game of the fourth set and another in the 12th.
The 30-year-old capitalised, sweeping the tie-breaker, topped off by a 13th ace of the contest.
But Cilic finished the fresher, breaking for a 3-2 lead and despite double-faulting on a fourth match point in the 10th game, he secured victory when Tsonga fired a forehand wide.
On Wednesday, five-time champion and second seed Roger Federer will face France's Richard Gasquet while French Open winner Stan Wawrinka takes on South African Kevin Anderson, the man who knocked out third seed Andy Murray in the fourth round.