In Thursday's draw, the No. 8 seed was placed in a tough second quarter that contains five former Grand Slam winners, including Serena herself:
Serena won her first title in almost three years on Sunday when she triumphed at the Auckland International, and the 38-year-old goes into the opening Grand Slam of the year as favourite.
Potapova, 18, will be an unknown for Williams as the pair have never met before in competition.
It would be a huge shock if the American did not breeze through her opening round at Melbourne Park.
Potapova has never made it past the second round of a Grand Slam and is ranked No. 90 in the world, 81 places below the seven-time Australian Open champion.
Williams' second-round opponent will be either Slovenia's Tamara Zidansek or South Korea's Han Na-lae, and in the third round, she is most likely to meet No. 27 seed Qiang Wang, who she thrashed 6-1, 6-0 in the quarter-finals of the 2019 U.S. Open.
It is the fourth round where things start to get interesting as the draw suggests a match against Britain's Johanna Konta.
Williams suffered the worst defeat of her career against the world No. 13 in 2018:
Assuming she can see off Konta, the veteran could then meet No. 3 seed and defending champion Naomi Osaka.
The Japanese star is one of few players to have the edge over Williams in their head-to-head. But in their last meeting, at the Rogers Cup in August, Serena won 6-3, 6-4.
Even if Osaka is upset in her run to the last eight, Williams' other potential quarter-final opponents are hardly easier.
An all-American clash is a strong possibility, as 26-year-old Sloane Stephens, No. 14 seed Sofia Kenin and 15-year-old sensation Coco Gauff are all in her quarter, as is her sister, Venus.
The semi-finals present a potential clash with world No. 1 Ashleigh Barty or last year's runner-up Petra Kvitova, who has prevailed against Williams in both their last two meetings.
Then finally, standing in the way of Serena levelling Margaret Court's record of 24 Grand Slam titles, is likely to be either Karolina Pliskova or Simona Halep.
The upshot of Thursday's draw is that Williams will need to get past a string of the world's best players in order to win in Melbourne, but that comes with the territory in a Grand Slam.
Most crucial for the American superstar will be avoiding mental and physical fatigue.
Since winning her last Grand Slam title, the 2017 Australian Open, when she was eight weeks pregnant, Williams has reached four further major finals, losing all of them. That is an unprecedented run in her career.
But last week's Auckland triumph, which put her back in the winner's circle, should give Williams a huge psychological boost and could pave the way for her to finally claim No. 24.