The 26-year-old sixth seed ran out of energy against third seed Stan Wawrinka, falling 4-6 7-5 6-4 6-2 on a hot, humid day at Flushing Meadows.
"I was definitely a little bit tired, especially in the end," Nishikori told reporters. "It's not easy after playing Andy five sets.
"He was playing much better the last couple sets. I stopped moving a little bit. He was playing powerful tennis."
Wawrinka advanced to Sunday's final against top-seeded defending champion Novak Djokovic.
Two years ago Nishikori charged all the way to the U.S. Open title match to become the first player from an Asian country to reach a grand slam final before losing to Marin Cilic.
"There was only two more matches to go, so I felt really close and playing at a good level I think these two weeks," Nishikori said about his goal of achieving a grand slam crown.
"It's not easy when you have to play number two, number three and (number one) Novak was waiting in the finals.
"It wasn't easy job, but if I could win a little easier the last few matches I could have little more chance today and maybe in the final."
Nishikori still took positives from the Open and his high calibre tennis the last couple of months.
"Beating Andy in this big tournament gives me confidence," he said. "Reaching the final in Toronto and bronze in the Olympics and semis here was a good summer."
(Editing by Sudipto Ganguly)
