The American top seed and 21-time Grand Slam winner wasted little energy in swatting aside the unseeded Russian 6-2, 6-1 in 55 minutes at Rod Laver Arena to set up the mouth-watering clash with her long-time rival.
Williams has won every game against Sharapova since 2004, including last year's final at Melbourne Park.
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Williams, who rarely looks at the draw during a tournament, claimed she didn't know who she was facing next.
"I had no idea," she said, when told Sharapova was up next by a courtside interviewer. "I really have nothing to lose. We're both just doing the best we can. It'll be fun."
The 34-year-old had schooled another Russian, Daria Kasatkina, in the earlier round, crushing her in just 44 minutes, and now it was the 58th-ranked Gasparyan's turn.
It was a sluggish start by Williams, who was broken in the first game by the 21-year-old on her tournament debut, to gasps of shock from the crowd.
But it was a minor blip as the top seed found her range, breaking straight back as the Russian found herself on the receiving end of Williams' powerful forehand.
Williams, with the great Margaret Court in the stadium watching, held serve and broke again for a 3-1 lead.
It wasn't vintage Serena but even operating at 50 percent she was too good for Gasparyan and a rout was on the cards.
Gasparyan, who won her first WTA title last year, at Baku, gamely hung on and held serve to keep the score respectable.
But the six-time Melbourne Park winner, gunning to equal Steffi Graf's Open-era record of 22 Grand Slam titles, was in full control, doing the necessary to take the set easily in 30 minutes.
She dropped just five games in her previous two matches and surrendered only one more against Gasparyan, breaking her on the fourth and sixth games with her phenomenal serve keeping her in command.
She wrapped it up with service winner down the line, clenching her fist in victory.
"I kinda knew she liked to go for a lot, to be aggressive, so I knew I had to play strong," she said of Gasparyan, who she beat at Wimbledon last year.
Williams won three majors -- the Australian and French Opens and Wimbledon -- in 2015 which took her to within one of Graf's long-time record of 22. Court holds the all-time Grand Slam record of 24.
The top seed claimed her first Australian Open title in 2003, beating sister Venus in the final, and reached her sixth last year when she toppled Sharapova.
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