Swiatek was swept aside by Jelena Ostapenko in the battle between two previous French Open champions in the desert.
Elina Svitolina, reigning Roland Garros champion Barbora Krejcikova and US Open runner-up Leylah Fernandez were also sent packing from the WTA Premier 1000 event.
After top seed Karolina Pliskova was eliminated on Monday, 2020 French Open champion Swiatek crashed out following a 6-4 6-3 defeat to Ostapenko.
Ostapenko – the 2017 Roland Garros winner – rallied from a break down in each set to reach the quarter-finals at Indian Wells, where the 24th seed hit 25 winners to 21 unforced errors in 93 minutes.
"I knew it was going to be a very tough match because she's such a great player, she won a grand slam and she's playing great tennis," Ostapenko said.
Standing in the way of Ostapenko and the semi-finals is Shelby Rodgers, who edged Flushing Meadows finalist Fernandez 2-6 6-1 7-6 (7-4).
SVITOLINA UPSTAGED BY PEGULA
Svitolina's campaign in the desert did not go according to plan, the fourth seed crushed 6-1 6-1 by Jessica Pegula.
Pegula – the 2021 Australian Open quarter-finalist – dismantled Svitolina in just 68 minutes for her seventh last-eight appearance of the season and fourth at WTA 1000 level.
"I think I've just been making a lot of really good decisions in the right moments," said Pegula, who will face two-time grand slam champion Victoria Azarenka following her seventh top-10 victory. "That obviously comes with playing a lot of matches, winning and getting confidence... it's just been more belief that I can play at this level. I think this year, I realised that, and I've been having good results."
KERBER POWERS THROUGH AS KREJCIKOVA FALLS
Three-time major winner and 10th seed Kerber will feature in the quarter-finals after overpowering Australian hope Ajla Tomljanovic 6-4 6-1.
Kerber will next meet 21st seed Paula Badosa, who shocked third seed and reigning French Open champion Krejcikova 6-1 7-5.
"I think I played a pretty good match today," Badosa said. "I knew I had to play on a high level against Barbora. She's an amazing player, very talented. We played before so I knew what I was going to find there on court. I'm feeling good and I'm very happy that I could play my best today."