Yet for all her myriad accomplishments, Williams says one of her "biggest ... and proudest moments" came Friday night -- in the second round of a tournament in Indian Wells, California.
It's not who she was playing, but where. The Indian Wells Tennis Garden is where Williams was booed during the 2001 finale. Her older sister, Venus, got similar treatment in the stands, and her father Richard told USA Today he was subjected to racial abuse.
Afterward, Serena Williams vowed she'd never go back. She kept true to that promise for 14 years, a time when she often dominated her sport.
On Friday, Williams was back. And instead of jeers, there were cheers.
And tears, shed by Williams during the crowd's loud, boisterous, more than minute-long ovation.
"I knew that I really wanted to do it," Williams said afterward of her return to Indian Wells. "But up until that moment, I didn't really know if it was the right thing for me to do.
"And I feel like that's when I felt it was the right thing," she said of her welcome. "... Receiving the love from the crowd here, it really meant a lot to me."
Father: 'Trouble holding back tears' after racist abuse
The BNP Paribas Open in Indian Wells, just east of Palm Desert, California, isn't a grand slam but is one of the top tournaments in tennis. As such, top players go there to battle the best and prove their mettle.
That's what brought Serena Williams to Indian Wells in 2001. The then-19-year-old got to the finals after her scheduled semifinal foe -- sister Venus -- pulled out minutes before the matching, citing a knee injury.
Amid whispers he'd predetermined the outcome, Richard Williams told USA Today that he "had trouble holding back tears" given the treatment he got in the stands. According to him, one man said, "I wish it was '75, we'd skin you alive." (Charlie Pasarell, the tournament director at the time, denied any racial abuse in the same story; CNN didn't hear back from him after requesting an interview.)
Serena Williams scored a three-set win over Kim Clijsters. But she didn't celebrate. She spent hours crying in the locker room.
"(I drove) back to Los Angeles feeling as if I had lost the biggest game ever -- not a mere tennis game but a bigger fight for equality," Serena Williams wrote in TIME magazine in February
. "Emotionally it seemed easier to stay away."
Williams feels like she's already won
The roller-coaster ride back to Indian Wells started when Williams accepted a wild-card invitation to play in this year's tournament, a difficult decision she recounted in TIME. Her father and sister, Venus, still stayed away.
While she's been on her sport's biggest stage for well over a decade, the world's No. 1-ranked played admitted being nervous in the weeks, days and hours leading to her opening match. Those feelings broke out in the open as she walked onto the court, a response she called "overwhelming" and said she "wasn't really prepared for."
The match itself wasn't easy, either.
Romanian-born Monica Niculescu, the world's 68th-ranked player
, challenged her for more than two hours. Still, Williams managed to overcome her competitor and her emotions to win in straight sets, 7-5, 7-5.
Declining to reflect on the past, Williams simply said afterward, "Today was a wonderful day for me, for women's tennis, ... for tennis in general, and for everyone."
The 33-year-old still has a lot of matches ahead of her. That includes more at Indian Wells, whose talented field includes Maria Sharapova and Caroline Wozniacki.
Still, for all her competitive fire, Williams isn't feeling much pressure to win. She feels like she has already won.
"I don't feel like I actually have to hold the trophy at the end of this," she said. "I feel like I'm already holding the trophy. And I've never felt this way.
'I feel like just being here is a huge win, not only for me but for so many people. And it's a wonderful feeling."