The World No 15 lost the first set on a tie break, but fought back to take the title after a thrilling 6-7 (8-6), 7-5, 6-4 victory.
In the first set she was 5-0 up and in the second she was 30-0 up at 5-1 before Mladenovic made a game of it. She was one point away from extending the lead when Pliskova's game started to click together and the Czech began to mount her comeback, saving set point to grab both breaks back.
The win marked the biggest title of Vesnina's career and she collapsed to the court with a mixture of ecstasy and exhaustion at the end.
Vesnina, a victor over world number one Angelique Kerber en route to the final, went 4-2 up in the first set courtesy of a fizzing backhand at the feet of the eighth seed, who netted.
Not only could fans be treated to a Stan Wawrinka-Roger Federer final showdown if things break the right way, but an all-Russian final between Svetlana Kuznetsova and Elena Vesnina on the women's side of the draw figures to be rather captivating.
The 24-year-old American notched his biggest singles victory yet with a 6-3, 2-6, 6-2 quarterfinal win over Kei Nishikori on Friday. I don't know how I won that game from 0-40, because she was fighting. It was her first time in the United States, and she was ranked around 250 in the world.
"I guess I'm on fire", Vesnina said. "I actually feel nearly stronger as the tournament has gone on".
Vesnina has done well to reach the final in Indian Wells which was certainly unexpected.
Neither Mladenovic nor Wozniacki had dropped a set before their quarterfinal. "She looked exhausted and slow on the court", Vesnina said. Painting the lines in the third set, Mladenovic broke twice and served out the two hour 33 minute win. "So I need to be aggressive and I need to dominate the points because he's really risky with his forehand". "It was a very important match for me".
The Russian lost in the first round of qualifying previous year but in the latter of half 2016 she reached her first Grand Slam semifinal at Wimbledon and finished ranked inside the top 20 for the first time in her career.
For Kuznetsova, it was a third disappointment in as many finals at Indian Wells, this one coming a decade after she fell in back to back finals in 2007 and 2008.