Cilic stepped onto the Grandstand court having won 16 straight sets at Flushing Meadows but that string quickly came to an end when the 56th-ranked Kukushkin took the opening set in a tiebreak in what was the start of a long and harrowing afternoon for the defending champion.
"I'm happy with the fighting spirit today, just accepting that I wasn't playing so well," said Cilic. "For sure (being defending champion) always has some weight to it.
"Playing on a big court with a full house, that's going to give you some extra motivation in the situations like today when I was a set and 5-2 down.
"I was in the thought process that I am going to stay on the court as much as necessary."
After crashing out in the first or second round of his last 16 tournaments, Kukushkin appeared determined to maintain an extended grand slam run following a second-round upset of 17th seed Grigor Dimitrov.
For four sets, the 27-year-old from Kazakhstan gave Cilic all he could handle and more but in the fifth he simply ran out of steam as the Croat surged ahead 5-0 before closing out the marathon encounter with his 27th ace.
"Today was very strange coming into the fourth set," said Cilic. "I felt that Mikhail was struggling a little bit physically and then I was really on top of him. Having a break up in the fourth, 15-40, few chances to go a double-break up.
"From then on things got complicated. He was making a lot of shots and just swinging. It wasn't easy to play.
"I didn't know actually what to expect."
(Editing by Mark Lamport-Stokes)
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