The three-time champion at Roland Garros will next take on Australian Ash Barty in the second round.
Krystina Pliskova, who shared the Wimbledon winners' stage with Serena back in 2010 - the Czech was junior champion as Serena won the real thing that year, played her part across the net on center court, but there was only one star.
"I'm just happy to win a match here, " Williams told the crowd in Court Philippe Chatrier.
It was the two-time French Open champion's first match on clay since 2016.
Williams is now tied, 2-2, in the first set.
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However, she gave a stinging response to the doubters on Tuesday even if her win over the 70th-ranked Pliskova tested the American. The Czech relies on her serve heavily, much like Williams, hitting 15 aces to Williams' 13.
Sharapova was given a tough challenge by Dutch qualifier Richel Hogenkamp but eventually prevailed 6-1, 4-6, 6-3.
Williams then took another break to work on her game, and that absence of more than two months ended Tuesday.
"She played really well", said Williams after the match.
Now ranked 43rd, the 32-year-old Kuznetsova was making her 16th consecutive appearance in the main draw in Paris. In the second set, the Chinese won just 10 points, and six came thanks to her opponent's unforced errors.
Making her eighth main draw appearance at Roland Garros (and ninth appearance overall), after her maiden major quarter-final reached a year ago, Garcia salvaged a slim chance of ascending to World No.1 this fortnight: she would need to win the title with Wozniacki not reaching R16, Halep losing before the semis and Muguruza going out before the final.
There were 28 aces in total during the match, with 17 of those coming in the first set.