It was only Osaka's third tournament back from an Achilles injury and it has been a stuttering return to action for the twice US Open champion, who also exited in the opening round in Toronto last week, retiring with lower back pain.
For Zhang, doubles champion in Cincinnati last year, it was her first singles win at the event since 2014.
"Naomi she is amazing but I don't know she is maybe not really feeling good today," said Zhang. "But for sure today - not her best today."
The first match on Centre Court, Japan's Osaka got the contest off to a sluggish start by double-faulting to gift Zhang a break on her opening serve.
That was all the help Zhang needed as she went on to take the first set with the 33-year-old Chinese player then quickly gaining the upper hand in the second with an early break to go ahead 2-1 as Osaka continued to misfire.
With Zhang serving for the match at 5-4, Osaka finally secured an elusive break to level the set only for her opponent to immediately break back and regain control.
Serving for the match a second time, Zhang did not squander the opportunity again, clinching victory with an ace.
Osaka got her serve working as she fired down 10 aces but not much else, with the four-time Grand Slam winner piling up 29 unforced errors and converting just one of four break chances.
Zhang next meets Russian Ekaterina Alexandrova who was a 6-4 7-5 winner over 13th-seeded Canadian Leylah Fernandez, losing finalist at last year's US Open.
This year's major at Flushing Meadows starts on Aug. 29.
