The world number three missed out on a first title of the season when he was beaten by Nick Kyrgios in the Mexican Open final on March 3 and he will not be adding to his list of honours at Indian Wells.
Struff saved all four break points he faced and took barely an hour to clinch his first career win over Zverev in five attempts 6-3 6-1.
Auger-Aliassime, who received a wild card into the draw after reaching his first ATP final at Rio de Janeiro last month, claimed his first win over a top-10 rival when he routed 10th-ranked Stefanos Tsitsipas 6-4, 6-2 in the second round.
Despite the circumstances, Struff was delighted to get a first win over Zverev. Before beginning his run in the desert last week, he owned a 1-3 record in Indian Wells.Struff dominated Zverev with his aggressive play from the baseline. "That hasn't changed unfortunately", Zverev, the world number three, said.More news: Gambino crime family boss fatally shot at Staten Island home
Zverev, the owner of three Masters 1000 titles who has never made it to the quarter-finals at Indian Wells, said he would now focus on recuperating and preparing for the Miami Masters, where he'll be hoping to improve on his runner-up finish to John Isner a year ago.
"I think I just got unlucky, I got a virus somewhere, and that's how it is", he said.
"He came up with the goods and definitely pushed me sort of to the brink there where I was getting a little bit frustrated", Raonic said. "He's such a good player, and I'm very happy that I could beat him". Then came Pune, and a three tie-break loss to Kevin Anderson in the final, followed by a second-round loss to No9 seed Kei Nishikori in Australia after nearly four hours and five sets.
Next up for 55th-ranked Struff will be Milos Raonic, who had his hands full before he overcame American qualifier Marcos Giron 4-6 6-4 6-4. "Here I have always struggled". "I just kept trying to plug away".More news: Luke Perry's Cause of Death Confirmed | Luke Perry
Zverev conceded after his second round virtual bye two days prior to feeling "probably the worst I have felt going into a match" and his condition was scarcely going to improve as Struff raised his level to open the second set.
The No18 seed has seldom looked more fit or more focused as he stacked up his 14th win of 2019 over Albert Ramos-Vinolas to reach the fourth round in Indian Wells, having won in Rotterdam and made the semis in Dubai.
It was a routine match for seventh seed Thiem, who defeated Gilles Simon 6-3 6-1.
Croatian veteran Karlovic is next up after the 40-year-old beat qualifier Prajnesh Gunneswaran 6-3 7-6 (7-3).More news: April Ryan: Sarah Sanders 'Is the Queen of Dodgeball’