Third seed Sharapova was first through to the final four after progressing past Kaia Kanepi 4-6 6-3 6-2 while Williams downed Dominika Cibulkova 6-3 6-3 to ensure the Queensland crowd will be treated to a blockbuster match-up.
Sharapova, though, will have to improve on her performance against Kanepi if she is to trouble the world number one come Friday.
The Russian world number four was not at her best in a scrappy last-eight clash but still managed to outlast her Estonian opponent to book a place in the semis.
In contrast to Williams' start, which she credited to the extra attention paid to her serve during the off-season, Sharapova's match began with four straight breaks of serve and she went on to total 17 unforced errors in the first set.
Had 2012 champion Kanepi been in better form herself - the match produced 66 clangers in total - the Sharapova-Williams semi-final match-up the tournament organisers had been hoping for would have been scuppered.
Sharapova, playing her first tournament in five months since recovering from a shoulder injury, looked rusty and struggled to find any kind of rhythm on serve.
Hard-hitting Kanepi, who won the tournament in Brisbane in 2012, took full advantage of Sharapova's sluggishness and claimed the first set.
But, after trading breaks at the beginning of the second, the Estonian double-faulted to gift Sharapova a 4-2 lead and from there the third seed did not relinquish her advantage.
The third set was a similar affair, with Kanepi allowing Sharapova to run away with the match after having been broken in the third game.
The Russian did improve as the match went on and in the third set her service accuracy improved to 84 percent, nearly double her efforts in the first two sets, but she knows her game needs plenty more improvement.
"You're going up against a great champion that's playing great tennis at the moment," Sharapova said.
"You know that you have to raise your level in order to beat her.
"I think the intensity level of our matches are always high. I think she goes up and wants to play the best tennis against me.
"That's certainly no secret because she shows that on the court."
Although the contests between the two have been one-sided, Sharapova herself says she needs "to win a few times in order to call it rivalry", the pair's frosty off-court relations ensured the clash is the biggest in the women's game.
When asked about her relationship with Williams following her victory over Kanepi, the Russian replied: "I have said everything I had to say about it."
The American, who has been at pains to discuss her more relaxed approach to tennis and life during the tournament, was slightly more forthcoming.
"I had a great talk with her," Williams said. "I don't have anything against her or anything."
Despite these protestations their body language is certain to be heavily scrutinised when they step onto Pat Rafter Arena on Friday.
Second seed Victoria Azarenka plays Stefanie Vogel for the right to meet Jelena Jankovic in the other half of what is a strong draw at the Australian Open warm-up event, after Jankovic beat Angelique Kerber of Germany 6-7(8) 6-3 6-1.
Across the Tasman Sea at WTA Auckland, second seed Ana Ivanovic booked a semi-final date with third seed Kirsten Flipkens after a comfortable 6-2 6-3 win over Kurumi Nara of Japan.
The Serbian world number 16 eased to victory in an hour and 16 minutes, setting up a meeting with Flipkens after the Belgian had accounted for another Japanese, Sachie Ishizu, 6-4 7-5.
Venus Williams also made the last four as she beat Garbiñe Muguruza 6-3 6-3. She goes on to play fellow American Jamie Hampton, who won through to the other final-four match-up with a 4-6 6-3 6-2 win over another American, Lauren Davis.
Brisbane International results
4-Jelena Jankovic (Serbia) beat 5-Angelique Kerber (Germany) 6-7(8) 6-3 6-1
1-Serena Williams (U.S.) beat 9-Dominika Cibulkova (Slovakia) 6-3 6-3
3-Maria Sharapova (Russia) beat Kaia Kanepi (Estonia) 4-6 6-3 6-2
Auckland Classic results
Venus Williams (U.S.) beat Garbine Muguruza Blanco (Spain) 6-3 6-3
5-Jamie Hampton (U.S.) beat Lauren Davis (U.S.) 6-2 4-6 6-4
2-Ana Ivanovic (Serbia) beat Kurumi Nara (Japan) 6-2 6-3
3-Kirsten Flipkens (Belgium) beat Sachie Ishizu (Japan) 6-4 7-5
Shenzhen Open results
Vania King (U.S.) beat Barbora Zahlavova Strycova (Czech Republic) 6-2 6-4
1-Li Na (China) beat Monica Niculescu (Romania) 7-5 4-6 6-4
5-Peng Shuai (China) beat Jana Cepelova (Slovakia) 6-3 6-2