Kerber, the No. 6 seed, held her own initially as the first six games were shared, but Osaka won nine of the next 10 with her power too much for Kerber to handle.
Day 1 of the U.S. Open is headlined by a first-round match between No. 2-seed Simona Halep and wildcard Maria Sharapova, who is playing in her first major tournament since returning from a 15-month doping ban in April.
Kerber becomes the first defending U.S. Open champion to lose in the first round the following year since Svetlana Kuznetsova was knocked off in round one in 2005.
French Open champion Jelena Ostapenko downed Spain's Lara Arruaberrena 6-2, 1-6, 6-1 in a match relocated from Court 17 to Ashe.
She said she had been practicing well and was confident, despite some minor nagging injuries that bothered her throughout the season.
In turn, Osaka has earned a victory that could propel her into the next tier of WTA players.
Only those matches scheduled for Arthur Ashe Stadium?were still planned for Tuesday. But it was in the following game that Osaka began to play some special tennis.
Brathwaite falls but Windies still have Hope in thrilling second Test
Brathwaite's 180-ball innings, including 12 fours, meant the opener had batted for more than 10 hours in the match. Appropriately, it was Hope who struck the winning runs with a legside flick for two off Chris Woakes.
There was better news for world number one Karolina Pliskova, who has headed in the opposite direction to Kerber after losing to the German in the final here past year.
The left-hander fell to 25-18 with no titles in 2017. Indeed a loss here would take her outside the top 10, and it was not an easy opener against teenage talent, Naomi Osaka. She had been in the top 10 since October 5, 2015, a run that will total 101 weeks before she falls out.
Osaka broke for a 5-3 lead in the first set, then seized control when she broke twice in the second set to open a 4-1 cushion.
The Japanese-American is a fearless ball-striker and Kerber had no answer, netting a final forehand to succumb meekly after just 65 minutes.
"I know that I'm strong and I know that I will come back stronger, for sure".
In other matches on the women's group, No. 23 seed Barbora Strycova defeated Misaki Doi of Japan, 6-1, 6-3, to reach the second round.
Information from The Associated Press was used in this report.