Williams gave birth to daughter Alexis Olympia in September and Thursday saw the American superstar back in a main draw of a WTA event for the first time since winning the 2017 Australian Open in Melbourne.
Sisters Serena and Venus Williams will collide at Indian Wells after they were both successful on Saturday night.
Serena, who lifted her 23rd Grand Slam title in Melbourne a year ago, was then already pregnant with daughter Alexis Olympia, who was born in September. "For me, it's a real joy to be out here", Serena said.
She joined American upset winners Sachia Vickery, who beat No. 3 seed Garbine Muguruza; 16-year-old wild card Amanda Anisimova, who beat No. 23 seed Anastasia Pavlyuchenkova; and wild-card teenager Caroline Dolehide, a three-set victor over No. 30 Dominika Cibulkova on Friday.
She featured in an exhibition match in Dubai and lost to Ostapenko and also played doubles with sister Venus in the Fed Cup.
Top-ranked Simona Halep beat Kristyna Pliskova 6-4, 6-4, and Petra Kvitova rallied past Yulia Putintseva 6-7 (4), 7-6 (3), 6-4 for her 14th consecutive match win.
Williams, though, as she often does, came roaring back to level things up after three games. Following the tournament, the sisters boycott the tournament for the next 14 years before Serena entered in 2015.
Venus said it looked like her sister had never been away.
The new mom is aiming to become the first woman to win three singles titles in Indian Wells, adding to her trophies from 1999 and 2001.
Second seed Caroline Wozniacki had an easy time with qualifer Lara Arruabarrena 6-4, 6-1. "I don't think my dad wants me to ever stop playing", the 37-year-old, seven-time Grand Slam champion said.
The breaks continued to go back and forth, with the second set seeing four in a row by the time the scoreline reached 3-3. The Dutchwoman was the better player early and served for the opening set at 5-4, but couldn't close falling in the end 7-6 (5), 7-5.
Wild card Danielle Collins defeated U.S. Open finalist Madison Keys 6-3, 7-6 (1) to continue a string of upsets.