Olympic champion Zheng looked out of sorts in the day's opening match on John Cain Arena, as Siegemund came out swinging and clinched a tight opening set in the tiebreak.
An early break in the next handed the German the advantage and although Chinese fifth seed Zheng battled back with one of her own, she quickly found herself 3-1 down.
World number 97 Siegemund delivered the final blow on serve to extinguish Zheng's bid to emulate compatriot Li Na's 2014 triumph at the year's first Grand Slam.
"I knew I just had to play more than my best tennis," said Siegemund, who earned her first top-10 win since 2022.
"I had nothing to lose so I told myself to swing free. She's an amazing player, she's one of the best players now. But I know I can play and I just wanted to make it a tough fight."
Zheng, who lost to Aryna Sabalenka in the title decider at Melbourne Park 12 months ago, said she had been bothered by some fitness issues after her run to the final of the WTA season-ending championship in November.
The 22-year-old felt she had not had the ideal build up to the year's first Grand Slam after having to miss tune-up events.
"For me, there was no chance to play a tournament before the Australian Open because the time was so rushed," said Zheng.
"I got some small issues after the WTA Finals. I discussed with my team if we have to come to the Australian Open or no.
"I'm the one forcing (them). My team said no. I've got to come here and try to play a slam. That's the tricky situation. There are issues in my body that haven't been solved yet."