Mladenovic's 94-minute victory booked her a blockbuster clash with Australian Open champion Osaka after she upstaged the Japanese star at the Dubai Tennis Championships in February.
The Swiss faced a dozen break points in the third set alone, including four at 6-5 as he tried to serve out the match.
Mannarino held a break point at 4-4 in the decider, and had a great look at a second serve, but he dumped a forehand into the net.
Osaka arrived at Indian Wells having played just the one match in Dubai since becoming world No 1 by winning the Australian Open in January.
"I struggled a little bit with my serving in that second set and that gave him chances".
Pliskova next faces another qualifier, Belgian Ysaline Bonaventure, who defeated 28th-seeded Donna Vekic of Croatia 1-6, 7-6 (7/5), 6-4.
In the press conference after her first win at the Indian Wells 2019, Osaka spoke about the inconveniences which are caused to her while playing night matches.
Kyrgios's title run in Mexico wasn't without controversy, with Nadal praising the mercurial Aussie's talent while also charging he "lacks respect for the public, the opponent and for himself". "I didn't really have a problem getting up". I took the first set.
Now a champion of 32 Masters 1000 titles, the Serb will be looking to win a sixth crown at Indian Wells - and provide a stark constrast in fortunes from his frustration this time previous year.
Donaldson could only take three games against Nadal in their only previous meeting in Shanghai in 2017, but he was unable to match even that. "I'd like to here that from the Council and some more players just to get a better idea of what is really going on", he added.
A runner-up in Rio and quarter-finalist in Sao Paulo, Auger-Aliassime, 18, claimed a 6-4 6-2 win over ninth seed Tsitsipas. It was the Indian Wells WTA triumph that proved to be the springboard of success for the 21-year-old as she went on to win the Australian Open which took her career rankings from 44th in the world to numero uno within a year.
Kecmanovic gained entry into the second round in place of injured fifth-seed Kevin Anderson.
At the other end of the age spectrum, 40-year-old Ivo Karlovic advanced with a 6-4, 7-6 (7/4) victory over 11th-seeded Croatian Borna Coric.
Zverev was leading Martin Klizan 6-3 2-0 when the Slovakian retired after less than an hour on court.