Fourth seed Ons Jabeur crashed out of the Miami Open on Friday, losing her opening match to Russian qualifier Varvara Gracheva 6-2, 6-2.
In another surprise, Canadian Bianca Andreescu, the former US Open winner now ranked 31st, overcame seventh seed Maria Sakkari of Greece 5-7, 6-3, 6-4, in a gruelling three-hour, three-minute battle in the early afternoon South Florida sun.
Romania's Sorana Cirstea upset world number four Caroline Garcia 6-2, 6-3 in a repeat of her Indian Wells win over the Frenchwoman last week.
But world number two Aryna Sabalenka got past American Shelby Rogers 6-4, 6-3, despite being hampered by what appeared to be a groin injury.
Tunisian Jabeur, beaten finalist at Wimbledon and the US Open last year, has been working her way back from injury and on her return earlier this month went out in the third round at Indian Wells.
Jabeur underwent surgery after suffering a knee injury at the Australian Open, and subsequently missed the WTA Tour's Middle East swing.
She looked well short of her best against the 22-year-old Gracheva and had two medical visits during the one-hour 11-minute match.
The win was the biggest scalp yet for Gracheva, who earlier this month reached her first WTA final, losing in Austin to Ukraine's Marta Kostyuk.
"The plan was, of course like all matches, to be as stable as possible, to try to make her work as much points as possible, and of course wait for comfortable ones to attack," Gracheva said after her third career win over a top 10 opponent.
"I've just probably caught this wave where I'm stable, where I always have a chance to play my game, be aggressive, cause troubles for the others by the game style. I've just got to try to keep rolling on this way," she added.
Andreescu, the US Open winner in 2019, had eliminated Britain's Emma Raducanu in the previous round and after losing the first set to Sakkari's powerful stroke play, the Canadian settled into a solid pattern of steady returns, peppered with aggressive winners as she took control of the second set.
She took advantage of some loose play from Sakkari but was unable to convert on two match-points at the end, offering a glimmer of hope to her opponent, but finally grabbed the win when the Greek found the net.
"I felt like I was on my heels a lot of the time during the match, but I made every ball," said Andreescu.
"I fought to the end, and I think I played the important points just a little bit better today. But it could have gone either way today," she added.
Andreescu has now claimed three wins over top 10 opponents since returning to the tour last April from a six-month mental-health related hiatus.
"I think it's just another step in gaining most of my confidence back," said the Canadian.
"I'm feeling really good on the court. I'm trying to be as fearless as I can be. It's not always easy, but I feel like I'm getting there, and wins like this obviously help," she added.
France's Garcia has suffered a slump in form since losing the final of the Monterrey Open in Mexico to Croatia's Donna Vekic.
Once again it was the 74th ranked Cirstea who provided her downfall with the Romanian rewarded for her aggressive stroke play.
Sabalenka needed lengthy medical treatment after being broken on the opening game of the second set against a determined Rogers and looked in discomfort throughout the rest of the match.
Despite the injury, Sabalenka was able to break back and see out the match and the Belarusian will face the Czech Republic's Marie Bouzkova next.
Karolina Pliskova of the Czech Republic advanced with a 6-2, 6-4 win over China's Wang Xinyu and her compatriot Barbora Krejcikova also enjoyed a straight sets win, 6-3, 6-2 against Belarusian Aliaksandra Sasnovic.