Having fallen outside the ATP’s top 40 for the first time since May 2018, Tsitsipas travelled to the prestigious Masters 1000 event in California needing a morale-boosting tournament.
Instead, the 27-year-old suffered a third straight defeat, with Canada's Denis Shapovalov proving too strong in a topsy-turvy 6-2, 3-6, 6-4 triumph.
Elsewhere, in the men's draw, Brazilian teenager Joao Fonseca secured a hard-fought 7-6(2), 6-4 victory over Raphael Collignon, while Italy's Matteo Berrettini came from a set down to outlast Adrian Mannarino 4-6, 7-5, 7-5 in just under three hours.
Gael Monfils, Jenson Brooksby and Gabriel Diallo were among the other notable names to make it through to the second round.
On the women's side of the tournament, 2019 champion Bianca Andreescu - who received a wildcard into the main draw - was beaten in three sets by Kamilla Rakhimova, 6-7(6), 6-0, 6-1.
Fellow big names Sloane Stephens and Paula Badosa also fell at the first hurdle in California, while Ukraine's Dayana Yastremska produced an accomplished display to see off Shuai Zhang, 6-3, 6-2.
Check out all the ATP and WTA results from Indian Wells via the links.