The fifth-seeded Zheng came into the first major of 2025 in imperious form.
In addition to her breakout run to last year's Open title match, Zheng made five more finals, won gold at the Paris Olympics and was runner-up to Coco Gauff at the showpiece season-ending championship.
But she was no match on Wednesday for the 36-year-old Siegemund - the oldest player still in the women's draw - who won 7-6 (7-3) 6-3 in two hours and 16 minutes.
It was the German's first win over a top-10 player since 2022.
Zheng Qinwen was no match for unheralded Laura Siegemund in the second round at the Open. (AP PHOTO)
"I knew I had to play more than my best tennis," Siegemund said in her on-court interview.
"I had nothing to lose, so I just told myself to swing freely.
"(Zheng) is an amazing player, just one of the best players right now.
"But I know that I can play well and I just wanted to show that to myself and make it a tough fight."
The woman who beat Zheng in last year's final at Melbourne Park, world No.1 Aryna Sabalenka, overcome a second-set scare to take another step on the road to becoming the first women this century to win three successive Australian Open crowns.
Unseeded Spaniard Jessica Bouzas Maneiro led 5-2 in the second set, only for the top seed from Belarus to step on the gas.
Sabalenka, 26, reeled off the last five games in succession to win 6-3 7-5 in one hour and 34 minutes.
Aryna Sabalenka reeled off the last five games to power into the third round at Melbourne Park. (James Ross/AAP PHOTOS)
"(Bouzas Maneiro) played incredible tennis today," Sabalenka said.
"It was a really tough one, I expected this tennis from her."
Next up for the Belarusian is a round-of-32 encounter with another unseeded player, Denmark's Clara Tauson, who trounced German Tatjana Maria 6-2 6-2.
Swiss superstar Martina Hingis was the most recent woman to lift the Daphne Akhurst Memorial Cup on three successive occasions in 1997-99.
Seventh-seeded American Jessica Pegula finally beat Elise Mertens for the first time in four attempts, knocking out the Belgian 6-4 6-2.
Mertens' best-ever performance at a major came at her Australian Open debut in 2018 when she made it all the way to the semis before bowing out to Carolina Wozniacki.
Pegula reached her maiden grand slam final at last year's US Open, where she lost to Sabalenka.
Serb Olga Danilovic caused a minor upset on Wednesday when she sent Russian No.25 seed Liudmila Samsonova packing 6-1 6-2.
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