Williams destroyed Barty for the loss of just three games in their only previous encounter, in the first round of the 2014 Australian Open.
The 36-year-old American had not played in one of tennis's biggest tournaments since winning the Australian Open in January 2017 for her 23rd grand slam title, breaking a tie with Steffi Graf for the most in the professional era.
The very first game featured an ace at 112 miles per hour (181 kph) and when it ended with Pliskova netting a backhand, the chair umpire intoned, "Jeu, Madame Williams", - French for "Game, Mrs. Williams", a change from the "Mademoiselle" officials use for unmarried female players.
Unseeded for the first time in Paris for the first time in a decade, Stosur clubbed 21 winners, five aces and broke Wickmayer five times in another typically strong start to her 14th Open campaign.
Barty, just 17 then and prior to an 18-month hiatus from tennis, has since established herself in the world's top 20 - and Williams is super wary of the threat the Australian poses.
The world No.25 looked like suffering her third consecutive first-round defeat at Roland Garros before turning the match around after a 45-minute rain delay.
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Considering he is averaging 34 points, 9.2 rebounds and 8.8 assists per game these playoffs, that at least feels possible. His top scoring average in the playoffs came in Cleveland in 2009, when he averaged 35.3 points a game over 14 games.
Only later did Williams reveal that she was pregnant at the time.
"I think we raised some real money", she laughed before making her way to the exit, stopping for selfies and to sign autographs for an appreciative French crowd.
"She played really well. I feel good and just so happy to be back here". Her baby was born on September 1, and Williams married Reddit co-founder Alexis Ohanian in November.
He blew a 5-2 advantage in the opening set, then a 3-1 buffer in the second. She's ranked No. 451 coming into the French Open.
"I call it my Wakanda-inspired catsuit", she said. "It's been a really long time but I trained really hard on the clay".
- Serena carves out first and only break point of the set but can not convert, sending the opener into a tiebreak.
"And obviously I want to talk to her about Serena because I think - I told her already a couple of things, but I think she has a good chance".