Austrian fifth seed Dominic Thiem made his second career recovery from two sets to love down to topple American qualifier Denis Kudla, 6-7 (6-8), 3-6, 6-3, 6-2, 6-3.
Frenchman Julien Benneteau stunned seventh seeded Belgian David Goffin 1-6, 7-6 (7-5), 6-1, 7-6 (7-4); 12th seeded Juan Martin del Potro got injury treatment on a hip but defeated young Russian Karen Khachanov 6-4, 7-6 (7-4), 6-7 (0-7), 6-4.
On the women's side, Taiwan's Hsieh Su-Wei claimed the biggest upset so far at the Australian Open, knocking out third seed Garbine Muguruza 7-6 (7-1), 6-4 in the second-round in draining heatwave conditions.
Top seed Simona Halep successfully tested an injured ankle under match conditions, producing a 6-2, 6-2 defeat of Canadian Eugenie Bouchard.
Halep rolled the ankle in her first-round win and was unsure of playing before making the call to go ahead.
"I still feel pain, and I couldn't practice much," she said. "But during the match, I just forgot about it. I had a very tight tape.
"The most important thing is that I could play my game not thinking about the ankle. I did that great today."
Reigning Wimbledon champion Muguruza came to the court with lingering fitness problems after cramping in matches in recent weeks, calling for her trainer as she faced the 88th-ranked Hsieh, a former doubles No. 1.
The problem turned out to be heat-related.
"It's blisters at the end, I think the surface of the court," Muguruza said. "I don't know how much heat, it's terrible, very, very hot, and it's easy to get blisters.