The Croatian lost 6-4, 5-7, 5-7, 4-6 at Flushing Meadows as his Argentinean opponent reached the last-16 of a Grand Slam for the first time.

He was broken nine times, including four times in the third set, and hit 80 unforced errors.

Having denied Cilic two break points in a tense final game, Schwartzman sealed victory after three hours and 23 minutes.

The result guarantees there will be a first-time US Open finalist with Cilic’s fellow top-10 seeds Alexander Zverev of Germany, Grigor Dimitrov of Bulgaria and Jo-Wilfried Tsonga of France all exiting the competition earlier in the week. 

"I think many players are doing well this week, and they are taking the opportunities because many players are injured this week," Schwartzman was quoted as saying by BBC Sport.

"I think we are trying to take the chances and trying to go forward in the tournament."

Cilic was playing in his first event since losing the Wimbledon final to Swiss legend Roger Federer in July, due to an adductor strain.

"[The injury] played a quite significant part [in the defeat], and just being injured and not being able to keep that good form," Cilic was reported as saying by BBC Sport.

"I was struggling with my shots and my serve was off."

Awaiting 29^th-ranked Schwartzman in the fourth round is 16th seed Lucas Pouille after the Frenchman beat Kazakhstan’s Mikhail Kukushkin 2-6, 6-3, 6-4, 6-4.

Another top-10 seed to crash out of the event today was the United States’ John Isner, who lost 4-6, 3-6, 6-7 to 23^rd-seeded German Mischa Zverev.

Isner's fellow countryman Sam Querrey progressed, however, with a 4-6, 6-2, 6-4, 6-4 victory over Moldova's Radu Albot.

Among the other winners today was 12^th-seeded Spaniard Pablo Carreño Busta, who defeated France’s Nicolas Mahut of France 6-3, 6-4, 6-3.

His next challenge will be Denis Shapovalov after the Canadian's opponent, Kyle Edmund of Great Britain, withdrew from their contest through injury when trailing 2-1 in sets.

Croatia's Borna Ćorić, who overcame fourth seed Alexander Zverev in the second round, lost to South Africa’s Kevin Anderson 4-6, 3-6, 2-6.

Anderson goes onto face Paolo Lorenzi after the Italian beat compatriot Thomas Fabbiano 6-2, 6-4, 6-4.

At 35 years of age, Lorenzi has become the oldest player in the Open Era to reach the last-16 at a Grand Slam for the first time.

In the women’s singles draw, two-time Wimbledon champion Petra Kvitová of Czech Republic moved into the fourth round with a 6-0, 6-4 win over France’s Caroline Garcia.

It was only the 19^th match of the year for Kvitová, who returned to action in May after an attacker at her home in December stabbed her in the hand.

"Sometimes I do feel a little bit more normal than before, especially on the court and around players and people, around tennis, which I'm very grateful that I can be part of it again," Kvitová was reported as saying by Sky Sports.

"Life is still a little bit strange, but it's getting better.

"Hopefully one day it will be better."

Kvitová will play third seed Garbiñe Muguruza of Spain for a place in the quarter-finals after the reigning Wimbledon champion cruised to a 6-1 6-1 victory over Slovakia's Magdaléna Rybáriková.

Muguruza, who is looking to make it back-to-back Grand Slam titles, will be competing in the fourth round of the US Open for the first time.

Among today’s other winners in the women’s singles draw was home favourite Sloane Stephens.

She beat Australia’s Ashleigh Barty 6-2, 6-4 and will next meet Germany’s Julia Georges, a 6-3, 6-3 victor at the expense of Serbia’s Aleksandra Krunić.

Spain’s Carla Suárez Navarro earned a spot in the last-16 with a 6-1, 3-6 6-3 win over Russia’s Ekaterina Makarova.

Two-time US Open champion Venus Williams stands between her and a place in the quarter-finals after the American defeated Greece’s Maria Sakkari 6-3, 6-4.