The 19-year-old from Japan rolled to a 6-3, 6-1 victory over the sixth-seeded Kerber at Arthur Ashe Stadium. Osaka landed 22 winners while overcoming 17 unforced errors.
"I just really want to play good here," Osaka said in a post-match television interview. "I played good today and so I hope to carry that on to my next match.
The victory was Osaka's first against a Top 10 player.
Meanwhile, top-seeded Karolina Pliskova faced little resistance in her opening-round match.
In her first match as the No. 1 seed at a Grand Slam, Pliskova recorded eight aces and 29 winners en route to breezing to a 6-2, 6-1 victory over Magda Linette of Poland.
The Czech needed just 38 minutes to win the first set against the 72nd-ranked player in the world. Pliskova continued on her quick pace, with the match only being slowed when the players were forced to break so the retractable roof at Arthur Ashe Stadium could be closed as a light rain fell.
Pliskova will face either Veronica Cepede Royg of Paraguay or American Nicole Gibbs in the second round.
Fellow Czech Barbora Strycova also advanced quickly to the second round, as the No. 23 seed cruised to a 6-1, 6-3 victory over Misaki Doi of Japan.
Also, Romania's Sorana Cirstea strolled to a 6-1, 6-3 win over Lesley Kerkhove of the Netherlands.