Sharapova has not beaten Williams since 2004 and has now lost 19 of their 21 match-ups overall as the American strolled to a 6-4 6-1 win on Rod Laver Arena.
The Russian had opportunities, most notably with two break points at the end of the first set, but Williams delivered at the decisive moment and it was one-way traffic thereafter.
Three out of Sharapova’s last five major tournaments have now been ended at the hands of the world number one, who goes through in Melbourne to face Poland’s Agnieszka Radwanska in the semi-finals.
“It’s obviously always frustrating,” Sharapova said.
“I mean, it’s motivating. It’s tough to sit here 30 minutes after the match and talk about the match, but that’s part of my job.
“It’s motivating because she’s at a different level. She makes you go back to the drawing board, not just for me, but for many other players. She makes you work. That’s inspiring.”
Sharapova served a career-best 21 aces against Belinda Bencic in the previous round but failed to penetrate Williams, who broke twice in each set.
“I think if you’re serving maybe 180 (km/hr) against somebody else compared to Serena, that’s an ace,” Sharapova said.
“Against Serena, as we all know, the return is one of her great strengths.
“She’s very explosive. She stays quite close to the baseline. She cuts the ball early. She doesn’t give you many angles.
“That’s the reason I can’t get so many free points against her.”
Williams started slowly and was certainly not at her barnstorming best but it is ominous for the rest of the draw that she won with so much to spare.
When it was put to her that there is clearly a big gap between her and Sharapova, Williams said: “There is. I don’t know. It’s something about her game.
“I like the way she hits the ball. Plus, when I play her, I know automatically I have to step up my game.
“I think that makes me play better. When I play better, when I’m forced to play better, I don’t know, I do well.”
Williams twice called for a trainer during the contest but allayed any concerns about injury, instead claiming she suffered food poisoning last week.
Radwanska eased past Spain’s Carla Suarez Navarro 6-1 6-3 but she has never beaten Williams in any of their eight previous meetings.
“It will be a good match,” Williams said. “She’s been playing really well towards the end of the year, and already this year she’s been very consistent.
“She presents a completely different game, an extremely exciting game. So I think it will be a long match and it will be a good match to see where I am.”