The American will face off with Anastasia Pavlyuchenkova on Tuesday, with either American Coco Vandeweghe or French Open champion Garbine Muguruza waiting in the last four.
If Williams gets through it will be her 20th time in the last four at a major. For the Russian, it will be the first.
Despite her lack of big-time success, Pavlyuchenkova feels that at 25 and with three Slam quarter-final appearances under her belt she is ready to take the next step.
"I definitely feel like I've been long enough on the tour, but at the same time I can't compare myself to Venus and Serena, because they have been there," said the 24th seed.
"I remember I was a little girl -- the racquet was bigger than me -- and they were ready to play in finals of a Grand Slam. So, of course, I can't compare myself to them, but at the same time I kind of also feel experienced.
"I have had some matches with Venus before, as well. I played her before, so I know how it feels to play against her. Let's see who's gonna win."
The pair have met five times before, with Williams, who is yet to drop a set in Melbourne, holding a 3-2 lead in their head-to-head, most recently a win in Montreal in 2014.
At 36, she is enjoying every moment of the tournament but also retains the hunger that drove her to seven Grand Slam titles, with the possibility of meeting sister Serena in the final an added incentive.
She is familiar with Pavlyuchenkova's game, and will be ready for whatever is thrown at her.
"I know her game. I have played a lot of matches this tournament kind of not knowing what to expect," said the 13th seed, having met two qualifiers and China's Duan Yingying, who she admitted knowing "zero" about.
"That can be a little -- it's a whole different approach.
"Now I have played her, I know what to expect. So I can almost already be settled in before I get to that match, so it's a good thing."
'Beat her to that punch'
In the other quarter-final on Tuesday, giant-killer Vandeweghe, who stunned world number one Angelique Kerber in the last round, meets seventh seed Muguruza.
The confident American, who also ended the comeback of Eugenie Bouchard en route to her first Australian quarter-final, has no fear of the Spaniard.
"It's just another person that's in front of me, whoever it may be, if it's number one in the world, number 130 in the world, it doesn't matter, it's still an opponent to get in my way of achieving my goals," she said.
Muguruza is an aggressive power-hitter, whose game has similarities to Vandeweghe.
"She is going to play that way, and no other way. For me it depends on if I can match it, as well as if I can beat her to that punch of getting first strike, first play," said the unseeded American.
Being in the last eight at Melbourne is also uncharted territory for Muguruza, who also yet to drop a set as she targets a second Grand Slam title.
She has played Vandeweghe twice before, with a win apiece.
"She's a tricky player, she has a lot of power, full shots, serve, everything,' she said.