Britain's former Grand Slam champion Raducanu is trying to find her form after multiple surgeries last year and played well but was unable to seize her opportunities, converting just one of 10 break points in her first meeting with Sabalenka.
The Belarusian, bedeviled by double faults in the past, issued one on her first match point but kept her composure and blasted a cross-court forehand winner on her fourth opportunity to seal the win under sunny skies in the California desert.
"I felt like the last game was kind of a key moment," said Sabalenka, who is seeded second.
"If I would lose that game this would give her emotionally much more belief and confidence, and going to the tiebreak you never know. It's like 50/50. I didn't want that to happen.
"That's why I felt a little bit of relief after I closed this match in two sets."
Sabalenka, who won her second straight Australian Open in January, will face American Emma Navarro in the Round of 16.
Mertens held her nerve to send Osaka packing with a gutsy 7-5, 6-4 victory over the Japanese player, who returned to the WTA Tour in January after a maternity break.
The Belgian, seeded 24th, had to fend off break points in the final game but ultimately prevailed, jumping in the air after claiming one of the biggest wins of her career and reaching the Round of 16 at the tournament for the first time.
Mertens will face a stiff test when she takes on third seed Coco Gauff.
Gauff did not play her best tennis but still managed to dispatch Italian Lucia Bronzetti 6-2, 7-6(5) in the American's last singles match as a teenager.
Bronzetti made the third seed work but Gauff saved 10 of the 11 break points she faced to advance to the fourth round where she faces Mertens, who has never beaten her, on her 20th birthday.
"Every time I play her is a tough match," Gauff said.
"I don't recall any straightforward wins playing against her. Even though the record is 3-0, it could easily have been the opposite.
"She's tough. She has good strokes and she can hit the ball clean, she can serve well, she makes you earn the match."
