Although her quest to become the first player in 27 years to win four majors in the same calendar year ended at the semifinals in New York, it proved her status as not just one of the world's greatest tennis players but also one of sport's biggest attractions.
But with the world No. 1 now on maternity leave, what impact will her absence have on the sport she has dominated since winning her first major at the 1999 US Open at the age of 17?
"Exceptional athletes with rare and unique talent come along once in a decade," said WTA spokeswoman Heather Bowler. "The WTA has had over four decades, each marked by exceptional players, so we know these great and new champions will emerge, some already are, and we look forward to the future."
Rising stars and comebacks
Williams, whose publicist confirmed last month she was expecting a child with her fiance, Reddit co-founder Alexis Ohanian, is due to give birth in the fall.
Williams' last slam victory was at the Australian Open in January, where she beat her sister Venus in the finals.
Although that victory meant she leapfrogged Steffi Graf as the most successful player of the Open era with 23 majors, she remains one shy of tying the all-time record of Australia's Margaret Court and has said she plans to return to tennis in 2018.
The WTA pointed to the emergence of young rising stars such as US Open finalist Karolina Pliskova and the returns this season of former grand slam winners Victoria Azarenka, Petra Kvitova and Maria Sharapova.
Azarenka of Belarus is due back from maternity leave this summer, while Czech Kvitova is recovering from a hand injury caused by an intruder in her house before Christmas. Sharapova, of Russia, made her comeback after serving a 15-month doping ban for the banned heart drug meldonium last month.
"These three tennis superstars are coming back into a highly competitive field of talent," Bowler said.
"No one is bigger than the sport"
Still, in the US, tennis' biggest market which was valued at $5.94 billion in 2015 by the Tennis Industry Association, no star shines brighter than Serena.
The 35-year-old is known by about two-thirds of Americans, according to the The Q Scores Co. in Manhasset, New York, which measures consumer appeal.
Five-time major winner Sharapova, a global star in her own right and the world's most marketable female athlete for 11 years running until her doping ban last year, is known by about 40% of the US population.
"Serena is a really important part of the sport, but I don't think anybody is bigger than the sport," said Tim Crow, chief executive of London-based sponsorship agency Synergy whose clients include Coca-Cola and Mastercard.
Fewer Tour events
In the past three seasons, Williams has drastically reduced her playing schedule as she chased Graf's record and her absence will be most strongly felt during the four majors -- the Australian, French and US Open and Wimbledon.
In recent years, The WTA has focused on local heroes with strong fan followings in their respective countries to grow TV audiences and increase ticket sales.
The likes of Denmark's former world No. 1 Caroline Wozniacki, Poland's 2012 Wimbedon finalist Agnieszka Radwanska, Puerto Rico's gold medalist Monica Puig, French Open winner Garbine Muguruza of Spain and two-time major winner Angelique Kerber of Germany have all been targeted.
In the past three years, with Williams less visible on the women's Tour, on-site attendances at WTA events have remained stable, according to Bowler.
Broadcasters also love a local hero.
With the newly formed WTA Media unit producing 2,000 live matches from this year under a multi-million agreement with Perform Group -- compared to 800 before -- international media rights to top-level women's matches have been sold to more than 115 countries.
WTA Media last year forecast a jump of close to 26% in potential audience growth for women's tennis to more than 567 million between 2017 and 2020.
The Kerber effect?
The emergence of 2016 Australian and US Open winner Kerber as the first German No. 1 since Graf has boosted audiences, sponsorship and reignited interested from broadcasters in Europe's biggest market for tennis.
For example, pan-European broadcaster Eurosport said 2.6 million Germans watched Kerber's surprise win over Williams in the 2016 Australian Open finals.
April's Porsche Grand Prix in Stuttgart sold out all of its sessions for the second year running as German crowds flocked to see Kerber and other local stars, such as eventual champion Laura Siegemund.
In addition, the return of Sharapova also boosted global television audiences.
After missing eleven months in 2010-11 because of foot surgery and illness, Williams kick-started her career in 2012 with the help of French coach Patrick Mouratoglou. The pair have since won 10 majors.
Williams' late-career renaissance has been important for tennis in her home country, where close to 18 million people regularly wield a racket.
"Despite a lack of Americans at the top of men's tennis -- John Isner was the highest-ranked American in the world rankings in 2016, in 19th -- the past five years, in which Williams has underlined her status as one of the greatest tennis players of all-time, has seen interest in tennis in the US rise from 24% to 36%," Nielsen Sports said in a report last year.
Although Court, Evonne Goolagong and Kim Clijsters all won majors after they had children, Williams turns 37 next year and will be entering what surely will be the final stretch of her impressive and record-breaking career.
Granted, there is only one Serena. But the next big female tennis star is probably already waiting in the wings.
"Tennis is a global phenomenon and has been for a long time," said Synergy's Crow.
"I remember when I was a kid, Bjorn Borg went and Jimmy Connors went and John McEnroe and it was 'how are we ever going to replace these guys?'," he said.
"Then Boris Becker came along, and Stefan Edberg came along and we did. And eventually we get Roger Federer. The baton just gets passed on."