"I definitely wasn't expecting or planning on dropping sets today", she said after a brief setback against Kuzmova.
At 37, Venus Williams is the oldest woman playing at the U.S. Open. "But things happen. That's why I play the match, because you have to win the match".
Nadal is a two-time victor of the U.S. Open, while Pliskova reached the final a year ago.
There, Williams used well-placed serves and her trademark power to close out the set 6-3, blasting a forehand victor past her young opponent to clinch the opening set.
Seeded ninth entering this year's Open, Williams maintained that her experience provides her clarity in understanding the necessities of navigating early round matches.
Serena Williams is absent from this year's U.S. Open as she prepares to have her first child but if there is to be an American champion at Flushing Meadows again it is still likely to be a Williams.
Garbine Muguruza, who won her second career Grand Slam title at Wimbledon and claimed her first WTA title on USA courts at Cincinnati, is also in the running. She made her first Grand Slam semifinal in January at the Australian Open, but has lost in the first or second round in all eight of her previous U.S. Open appearances.
Not that it was foremost on her mind.
She said in the past, she struggled to find her rhythm at Flushing Meadows.
"I just want to win, and if you get the win, you get the ranking", said Williams, who was previously at No.1 in 2002.
Before the American's match was over, that number of No.1 ranking contenders was reduced to seven, because the No. 7-seeded Johanna Konta was bounced by 78th-ranked Aleksandra Krunic of Serbia 4-6 6-3 6-4.
Rafael Nadal and Karolina Pliskova are the top two seeds in the men's and women's singles draws, respectively.
"We always coach each other, pretty much", Williams said.
After the clinching point, Sharapova, the 2006 U.S. Open women's champion, fell to her knees and wept. On the women's side, there as No. 21 Ana Konjuh, No. 24 Kiki Bertens and No. 32 Lauren Davis.