Osaka, who grew up in NY, broke for 5-3 and sealed the opening set with a sizzling victor down the line under the closed roof at Arthur Ashe Stadium. "But at the end, I know that I'm strong and I know that I will come back stronger, for sure".
A double-fault set up the teenager's only break point and a backhand error in the ensuing point from Kerber gave Osaka the break.
But perhaps it wasn't so surprising after Kerber played so poorly after her breakthrough 2016, when she also won the Australian Open and lost to Serena Williams in the Wimbledon final.
She led Madison Keys 5-1 in the deciding set of their third-round clash on Ashe a year ago only to lose in a deciding tie-break.
Kerber rose to the top of rankings after winning in both Australia and NY last season but has not claimed a title since nor made a grand slam quarter-final.
"She just goes for it", added Kerber.
This year, she fell in the first round of the French Open, that first time that had ever happened to the women's No. 1 seed in that tournament.
And arguably, it all started here for the 25-year-old in a final finish that took in wins over both Williams sisters.
Nadal, this year's French Open champion, is 12-0 in first round meetings in NY while Federer is 16-0.
In the day's other matches, Czech 23rd seed Barbora Strycova dispatched Misaki Doi 6-1 6-3, Yanina Wickmayer upset 28th-ranked Lesya Tsurenko 6-3 6-1, and Sorana Cirstea from Romania beat Lesley Kerkhove 6-1 6-3. This time, she would not make the same mistake, in a devastating display of aggressive baseline tennis.
World number one Karolina Pliskova, bidding to back up her lofty status with a maiden first Grand Slam title, made a winning start at a soggy US Open on Tuesday as Rafael Nadal and Roger Federer waited to begin their campaigns.
Angelique Kerber insisted she can return to the level that made her a two-time grand slam champion and world number one after a disappointing season hit a new low. This was their first career meeting.
She next faces either Swedish qualifier Rebecca Peterson or Czech Denisa Allertova, with a potential fourth-round clash against French Open champion Jelena Ostapenko looming.
Juan Martin del Potro, the 2009 champion in NY, starts against Switzerland's Henri Laaksonen.
The Ashe programme Tuesday was being completed by United States 15th seed Madison Keys facing Elie Mertens of Belgium.