Stefanos Tsitsipas and Taylor Fritz fall to defeats on day of first round shocks at Japan Open
Top seed Fritz, who this month became the first American man to reach a Grand Slam final since 2009, was bundled out 6-4, 3-6, 6-3 by France's Arthur Fils.
It came just hours after number seven seed Tiafoe, who lost to Fritz in the US Open semi-finals, was eliminated with a 7-5, 6-3 loss to fellow American Brandon Nakashima.
Tsitsipas, the world number 12, took the first set in Tokyo but had no answer to his 49th-ranked opponent for the rest of the match, losing in one hour and 48 minutes.
World number seven Fritz won the Japan Open title in 2022 but met his match in the energetic 20-year-old Fils.
Fritz needed a medical time-out to deal with a back issue during the second set.
He could not recover as world number 24 Fils closed out the match in just over two hours to set up a second-round match with Italy's Matteo Berrettini.
Tsitsipas's woes deepened after losing to world number 49 Michelsen.
The Greek world number 12 took the first set but had no answer to his 49th-ranked opponent for the rest of the match, losing in 1hr 48min.
A two-time Grand Slam finalist, Tsitsipas was bundled out in the first round at the US Open last month after ending his long-time coaching collaboration with his father, Apostolos.
Tsitsipas said after losing to Australian Thanasi Kokkinakis at the US Open that he was "nothing compared to the player I was before", speaking of "long-term burnout".
The former world number three has slipped out of the top 10 and has won just two titles in two seasons.
Defending Japan Open champion Ben Shelton went through with a 3-6, 6-1, 6-4 win over fellow American Reilly Opelka.
Number eight seed Shelton, who will play Argentina's Mariano Navone in the second round, said "this is a part of the year where I play very, very well".
"I don't feel pressure as the defending champion," said Shelton, the world number 17.
"It makes me feel more confident and comfortable playing this tournament."
Britain's US Open semi-finalist Jack Draper also advanced in Tokyo after beating Italian qualifier Mattia Bellucci 6-4, 6-2.
American Tommy Paul, the number five seed, beat Italy's Matteo Arnaldi 6-3, 6-2.
Number six seed Holger Rune of Denmark outlasted Chile's Alejandro Tabilo 6-2, 5-7, 6-4, while Japan's Yoshihito Nishioka edged Canada's Felix Auger-Aliassime 7-6(5), 3-6, 7-6(5) in a match that lasted three hours and 12 minutes.