Williams will be walking out for her 47th grand slam quarter-final while Konta is playing her second, and the American is also gunning for an Open era record 23rd major title in Melbourne.
“I have absolutely nothing to lose in this tournament,” Williams said. “Everything here is a bonus for me.
“Obviously I’m here to win. Hopefully I can play better. I can only go better.”
One more triumph would pull Williams clear of Steffi Graf and just one short of Margaret Court in the all-time list.
It would also see her reclaim the world number one ranking after the current incumbent Angelique Kerber was beaten in the fourth round by Coco Vandeweghe.
Williams moved one step closer with a 7-5 6-4 victory over 16th seed Barbora Strycova and now faces Konta, the in-form British number one, for a place in the last four.
Williams chose not to play another match last year after the US Open in September, deciding instead to recover from niggling injuries and recuperate.
She then endured a second-round loss at her comeback in Auckland earlier this month, prompting doubts about her fitness and form.
Into the quarter-finals, however, and without dropping a set, Williams is now the clear favourite to collect a seventh Australian Open title.
She has never played Konta but is aware of her opponent’s remarkable rise, the Briton chasing her 12th consecutive win after winning the Sydney International a fortnight ago.
Williams will be hoping to avoid another upset at Melbourne Park, where the top two seeds in the men’s draw - Andy Murray and Novak Djokovic - have both crashed out, as well as Kerber in the women’s.
Defeat for Williams would make it the first grand slam since the 2004 French Open that the top two seeds in both singles draws failed to make the semi-finals.
“Murray was very shocking. I went to bed by the time the other match came on, because it was getting to be so late - believe it or not, I’m still slightly jet lagged,” Williams said.
“But it’s been a couple of interesting weeks for Angie. You know, she’s been dealing with a lot. I think she was able to handle it the best she could.
“I think Coco played really well. I think she really just came up with a wonderful game plan and it was an easy match so it wasn’t too surprising.”
Meanwhile Rafa Nadal returned to the grand slam big-time by weathering a furious Gael Monfils fightback to win 6-3 6-3 4-6 6-4 and reach the Australian Open quarter-finals.
Former champion Nadal had not reached the last eight in a major since the 2015 French Open, so he celebrated wildly after closing out the two-hour 56-minute clash at a packed Rod Laver Arena.
It was not the most convincing of wins for the 30-year-old Spaniard, who became rattled when sixth seed Monfils rallied brilliantly in the third set and went up 4-2 in the fourth.
But Nadal summoned the resilience of his halcyon days to win four straight games and keep his pursuit of a 15th grand slam title alive.
Novak Djokovic may be absent after his shock second-round elimination but third seed Milos Raonic looms as a massive roadblock to Mallorcan star Nadal’s hopes of a first grand slam semi-final since winning his last French Open in 2014.
“For me, it means a lot because I really start the season playing quarter-finals in a grand slam again, especially on a hard court (and) after a couple of years without being in this round is great news,” ninth seed Nadal said.
“Very happy with an important victory against a very good opponent.”