But Australian Open champion Madison Keys, also defending her crown in Adelaide, has moved safely through to the quarter-finals.
Russian-born Kasatkina fell to world No.35 Jaqueline Cristian 6-4 6-0 on Wednesday, the disappointment coming after booking a rousing first win in front of her new home fans.
Eight double faults meant the newly-minted Australian struggled to build her rhythm on centre court, with the match wrapped up in 91 minutes.
It was the Romanian's first win over Kasatkina in three attempts, continuing her strong form after eliminating fourth-seeded Russian Ekaterina Alexandrova in the first round.
Former world No.8 Kasatkina, now ranked No.48, is on the comeback trail after ending her 2025 season in October to take a mental-health break.
She switched allegiances in March last year because of discrimination against the LGBTQI community in her native country.
Keys also had early serve troubles, and was forced to overcome seven first set double faults to secure a 6-4 6-1 win over Czech teenager Tereza Valentova.
The 30-year-old American improved that statistic in the second set and broke the Valentova twice for what ended up being a comfortable win.
"I was able to take momentum in the second set and play really well. I had to raise my level. You have to take your chances on any opportunities you get," Keys said.
Ninth seed at the Open, Keys will next face another 18-year-old in Adelaide, taking on Victoria Mboko.
The promising Canadian announced herself on the world stage last year by winning the WTA 1000 title in Montreal and the Hong Kong Open.
Keys began her 2026 Australian Open preparations last week in Brisbane, losing in the quarter-finals to world No.1 Aryna Sabalenka in a rematch of last year's Australian Open final.
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