But to do so, the 34-year-old American will have to achieve something she has so far failed to manage -- defend her crown in Paris.
Just three of Williams' 21 Grand Slam titles have come in France -- the first in 2002 and then a long gap until 2013 and 2015.
The year after her inaugural French Open title, she lost in three tough sets to eventual winner Justine Henin -- hardly a major upset at that time.
That defeat to the lowly-ranked French player resulted in Williams re-dedicating herself to the game under the guidance of French coach Patrick Mouratoglou.
The result has been spectacular with her winning two Wimbledon titles, three consecutive US Opens between 2012 and 2014, one further championship in Paris and the Australian Open in 2015.
Williams, who won her first title in nine months in Rome last weekend, will begin her Paris defence against Slovakia's Magdalena Rybarikova, the world number 76, who has yet to make it beyond the second round.
"I think now it's different because I want to win more than I think most people ever, but also I think it's different now because I don't have anything to prove and I don't have anything -- it's just a different feeling," she said.
"Whereas five, ten years ago, oh, I'm defending and I feel that pressure. Now it's like I'm defending, I'm in Paris, it's cool, and I'm having, you know, the time of my life. I'm just happy to be here."
The victory in Italy came at an opportune moment for Williams as she had gone title-less since Cincinnati in the buildup to last year's US Open.
A fourth round loss to Svetlana Kuznetsova at Miami saw Williams pull down the shutters for a while only for her to roar back to form in Rome.
- Emerging threat -
===================
With two-time winner Maria Sharapova out of the picture under a doping cloud, the opposition to Williams is expected to come from Europeans in the shape of Germany's Angelique Kerber, who upset Williams in Melbourne, two-time Wimbledon champion Petra Kvitova of the Czech Republic, 2014 finalist Simona Halep of Romania, Poland's Agnieszka Radwanska, as well as Azarenka.
Former world number one and two-time Australian Open winner Azarenka is a potential quarter-final foe for Williams while 2010 French Open champion could be a third round opponent.
Fifth seed Azarenka, a semi-finalist in 2013, opens against Italy's Karin Knapp.
Second seed Radwanska is scheduled to face Halep in the last eight. Radwanska, yet to get past the quarter-finals, takes on Serbia's Bojana Jovanovski first up.
Kerber starts against Dutchwoman Kiki Bertens.
Wimbledon finalist Muguruza and US Open runner-up Roberta Vinci is the other potential quarter-final if seedings go to plan.
