French Open finalist Tsitsipas, enjoying the best campaign of his career to date, had been targeting Wimbledon glory as his No1 priority for the season.
But in what had the potential to be one of the most eye-watering opening-round ties, the Greek was always playing second fiddle to Tiafoe.
It was the third time in four Wimbledon appearances that Tsitsipas has failed to make it out of the opening round, a mystifying statistic for a player that appears to have all the attributes to make his mark on grass.
The shocks weren’t reserved for the men as two-time women’s champion Petra Kvitova was beaten moments later 6-3 6-4 by Sloane Stephens.
Elsewhere in the women’s singles, there were losses for Britons Katie Swan and Jodie Burrage.
Swan had done so well to come through qualifying to take a lucrative place in the main draw but was outmatched 6-3 6-4 by No23 seed Madison Keys.
Meanwhile, Burrage struggled to make inroads against Keys’ fellow American Lauren Davis, losing 6-2 6-1.
But there was brighter news for Katie Boulter, the first British winner at this year’s tournament, edging Danielle Lao 6-7 6-3 6-4. She next faces No2 seed Aryna Sabalenka.