Nothing went right for the British number one in a 6-1 6-1 loss that lasted 54 minutes.
Watson has had a stellar season, climbing from a low of 161 in the rankings at the start of February to 46 and posting her first two wins over top-20 players.
Cirstea, on the other hand, has slumped from 21 a year ago to 80 and this looked a good first-round draw for Watson.
But the Romanian began the match showing form of old, thumping aces and forehands and leaving Watson reeling.
It did not help that the British player, who has developed her own attacking game to great effect this season, was struggling to find her first serve.
Watson had beaten Cirstea in their three previous meetings, most recently in Fed Cup earlier this year, and in 2012 in Miami she won from 5-0 down in the deciding set.
But a comeback never looked on the cards this time and Cirstea took her first match point with another forehand winner.
Watson's statistics made miserable reading, with eight double faults, six winners and 23 unforced errors adding up to a very bad day at the office.
The 22-year-old still has not won a match at Flushing Meadows since winning the junior title in 2009 and will look to put this one behind her quickly.
Her defeat leaves Andy Murray once again as the only British singles player left in the tournament.
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