Williams, 40, struggled to find consistency in just her fourth match of the season, giving up 12 unforced errors while making just 11 winners in the first round of the Western and Southern Open in Cincinnati..
Meanwhile, the 10th-seeded Brit settled in to her rhythm early, breaking the 23-time major champion twice in the opening set before racing away in the second to claim her 12th win of the season.
The 19-year-old paid tribute to Williams in her on-court interview after the match.
“I think we all need to just honour Serena and her amazing career,” she said.
“I’m so grateful for the experience of being able to play her and for our careers to cross over.
“Everything that she’s achieved is so inspirational and it was a true honour to share the court with her.”