Osaka beat Mladenovic 6-3, 6-4, the win under the stadium court lights sweet revenge for the reigning US and Australian Open champion after she lost to the same opponent in the Dubai Duty Free Tennis Championships first round last month.
Venus Williams fought back to down third seed Petra Kvitova 4-6, 7-5, 6-4 and reach the BNP Paribas Open third round on Saturday, while Naomi Osaka got her title defence off to a flying start with a straight sets win over Kristina Mladenovic.
World number one Osaka beat Mladenovic 6-3, 6-4, the win under the stadium court lights sweet revenge for the reigning US and Australian Open champion after she lost to the same opponent in the Dubai Duty Free Tennis Championships first round last month.
Osaka said it was the first time she had felt the pressure of defending a title.
"I've never been a defending champion before so I was pretty nervous and I'm glad I got the win," the Japanese 21-year-old said.
American Williams, 38, turned back the clock in the final two sets at Indian Wells, dialling up the speed on her first serves and playing stout defence to seal a win that looked unlikely when she was down a double break in the second set.
The seven-times Grand Slam champion threw her arms in the air and let out a roar when Kvitova sent a ball long on match point -- the Czech's 56th unforced error of the day.
Williams tipped her hat to the two-times Wimbledon champion after the hard-fought contest.
"She has been playing so well and you never know what's going to come off her racket," a beaming Williams said in front of a fawning crowd as night fell on her native Southern California.
"I was just happy to have your energy to get pumped up. I just love the battle."
Earlier, another American, Madison Keys, blew a late lead to fall 3-6, 6-1, 7-5 to German Mona Barthel.
The 17th-seed had the match on her racket serving with a 5-4 lead in the third set but lost three straight games, including her final service game to love, allowing the unseeded Barthel to advance.
Next up for Barthel is a meeting with countrywoman Julia Gorges, who beat Estonian Kaia Kanepi 6-3, 2-6, 6-3 behind seven aces in an evening match.
Unheralded Russian Ekaterina Alexandrova upset former world number one Caroline Wozniacki 7-5, 2-6, 7-5 in a battle that lasted nearly two-and-a-half hours in the evening session.
Alexandrova put her hands over her face in disbelief when Wozniacki was unable to return her serve on match point.
The 24-year-old will face Belinda Bencic in the third round on Monday after the Swiss cruised to a 6-4, 6-1 win earlier in the day.
Former world number one Angelique Kerber was nearly perfect en route to a 6-0, 6-2 dismantling of Yulia Putintseva, winning 93 per cent of her first service points under sunny skies.
The eighth seed will meet red-hot Russian Natalia Vikhlyantseva in the third round after the qualifier crushed Spaniard Carla Suarez Navarro 6-2, 6-0.
Czech Karolina Pliskova, Latvian Anastasija Sevastova and Americans Danielle Collins and Christina McHale were among the other players who prevailed in their second-round matches on Saturday.