With No. 14 John Isner and Tennys Sandgren both losing Saturday, the US Open is without an American in the men's draw heading into the round of 16 for just the third time in the Open era.
The U.S. men haven't won a major title since Andy Roddick won the US Open in 2003. The 63-major drought is the longest American men have gone without a major in U.S. tennis history.
Isner lost to former Flushing Meadows champ Marin Cilic 7-5, 3-6, 7-6(6), 6-4, and Sandgren lost in straight sets to Diego Schwartzman.
Cilic earned the crucial break in the fourth set to get the advantage over Isner. The American fought back with a pair of match points before Cilic finally put it away on his serve to advance to a Grand Slam tournament fourth round for the 23rd time.
Isner finished the day with 40 aces and only four double faults. Cilic had 21 aces but 17 double faults. Both players converted on about 80% of their first-serve points, but Cilic saved 13 of 14 break point chances.
Cilic will next face Rafael Nadal, who had no trouble downing qualifier Hyeon Chung 6-3, 6-4, 6-2 to reach the U.S. Open round of 16 -- the 13th straight time he has gone at least that far in a Grand Slam event.
The No. 2-seeded Nadal has had a relatively easy journey at Flushing Meadows so far, receiving a walkover in the second round from Thanasi Kokkinakis due to an injury and not dropping a set in his other two matches.
Against the 170th-ranked Chung, a 2018 Australian Open semifinalist who has battled injuries, Nadal played an aggressive game off the ground and on the serve, winning nearly 90% of his first-serve points.
In other men's matches on Saturday, No. 24 Matteo Berrettini took care of Alexei Popyrin in four sets, and 33-year-old Pablo Andujar beat Alexander Bublik to reach the fourth round of the US Open for the first time.
German Alexander Zverev is also heading into the second week at Flushing Meadows for the first time after taking care of Aljaz Bedene 6-7, 7-6, 6-3, 7-6.
The Associated Press contributed to this report.