The 26-year-old Paire, having collected his maiden ATP Tour title last month in Bastad, brought his good from to Flushing Meadows grinding out a three hour 14 minute victory to get the season's final grand slam off to a shocking start.
"It's always very sad to lose in the first round, but I think he was playing good tennis," said Nishikori.
"I don't think I played badly. Didn't play great, but still, it's never easy first match."
Japan's Nishikori, whose run last year included gruelling five-set wins over Milos Raonic and Stan Wawrinka and a shock victory over world No 1 Novak Djokovic, had looked ready to survive the opening test coming back from a wobbly first set.
But after the 41st ranked Paire fought off two match points to take the fourth set tiebreak 8-6 then carried the momentum into the fifth set where he recorded the decisive break to go up 3-2 before finishing off Nishikori with a thundering ace.
"I had match point and I kind of lost a little bit my forehand," said Nishikori.
"I mean, tiebreak can go both ways so maybe I lost a little bit of concentration but he was hitting good serves, too.
"Especially the first couple games in the fifth set, I lost my concentration and he returned well, too. I mean, credit for him, too, playing good tennis with these conditions."
A three-time winner on the ATP Tour this season, Nishikori arrived at Flushing Meadows as one of the favourites to capture the year's last grand slam.
After a sluggish start, the 25-year-old slowly found his rhythm taking the next two sets and then looked ready to advance after going up 6-4 in the tiebreak.
Paire, however, swept the next four points before letting out a mighty roar as the match went to a fifth set.
"To beat Nishikori for me, was impossible to imagine this," said Paire, who entered the match with an uninspiring 2-16 record against top-10 ranked opponents.
