The Belarusian has been trying to turn around a dismal second half of the season, having failed to reach a final since winning at Indian Wells and the Miami Open to complete the Sunshine Double in March.
She seemed well on her way to flipping the script with the crowd on her side at Arthur Ashe Stadium.
Sabalenka, who would join Serena Williams and Chris Evert as the only women to win three straight US Opens in the professional era, fired off 32 winners to set up a meeting with Russian Polina Iatcenko in the second round.
"I'm super happy with the level I played," said Sabalenka. "I feel like this is one of my favourite stadiums, I really experienced the best emotions here on this stadium."
Osorio handed Sabalenka a break with a double fault in the third game - one of five she had across the opening set - and slipped 4-1 behind as the Belarusian converted on another break point with an unreturnable backhand.
The Colombian trimmed the lead to 4-2 in the next game but never got a hold of the momentum and her racket went flying in her futile attempt to reach Sabalenka's perfectly placed drop shot on break point in the seventh game.
After trading early breaks in the second set, Sabalenka wore down her opponent's defence to secure the pivotal break in the ninth game, before closing it out with an unreturnable serve and a subdued celebration.
Sabalenka is also defending her world number one ranking in New York, with three other players in the women's main draw in a position to overtake her.
US Open 2026
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