"I think taking a break and going to change -- I was completely wet -- I was refreshed," Tsitsipas said when asked about the key to sweeping the final set in 30 minutes.
"I was much more able to deliver good tennis in the fourth set. I was able to stay resilient on each and every point."
Tsitsipas, who matched his deepest US Open run, has been ridiculed by Andy Murray and Alexander Zverev for extended bathroom breaks seen as gamesmanship.
French Open runner-up Tsitsipas, who says he's only following ATP rules that have no time limit on toilet breaks, fired a career-high 27 aces, five more than his previous best, in winning his ATP-best 50th match of the year.
"I just felt very loose on my serve," Tsitsipas said. "My ball toss was very consistent. That helped me find a spot and have points off my serve."
High winds and water drenched the grounds and wind-blown rain entered through upper corner openings under the closed roof of Louis Armstrong Stadium to suspend a second-round match between South African Kevin Anderson and Argentina's Diego Schwartzmann.
Remnants of deadly Hurricane Ida would shut down the covered court after twice interrupting the match, with the National Weather Service issuing a tornado and flash flood warnings for the area.
Anderson and Schwartzman resumed in Ashe after Tsitsipas's victory.
Walkover for Osaka
Defending champion Naomi Osaka advanced by walkover while Russian second seed Daniil Medvedev breezed into the third round over Germany's Dominik Koepfer 6-4, 6-1, 6-2.
Osaka reached the third round when 20-year-old Serbian qualifier Olga Danilovic withdrew due to illness.
"I have been feeling unwell these past few days dealing with a non-covid related viral ilness," Danilovic posted on social media.
Osaka, seeking her fifth Grand Slam title and third US Open crown in four years, next faces Canada's 73rd-ranked Leylah Fernandez.
The 23-year-old Japanese third seed could could become the first repeat US Open winner since Serena Williams, absent with a torn hamstring, captured her third in a row in 2014.
Sloane Stephens, the 2017 US Open winner who could meet Osaka in the fourth round, beat 21st seed Coco Gauff 6-4, 6-2 in an all-American showdown.
"I'm really pleased with how I played," Stephens said.
Medvedev, a winner last month in Toronto, also beat Koepfer on his way to the 2019 US Open final, which he lost to Rafael Nadal.
"Great level from me," Medvedev said. "There were a few tight moments in the match and I managed to play them well. I'm happy to be through in less than two hours."
Russian fifth seed Andrey Rublev beat Spain's Pedro Martinez 7-6 (7/2), 6-7 (5/7), 6-1, 6-1. He next faces 50th-ranked American Frances Tiafoe, who warns, "I'm coming after him."
Two-time Grand Slam winners Victoria Azarenka and Garbine Muguruza booked a third-round showdown.
Spanish ninth seed Muguruza, the 2016 French Open and 2017 Wimbledon winner, beat Andrea Petkovic 6-4, 6-2, taking her first win in four tries against the German.
She will next face two-time Australian Open champion and three-time US Open runner-up Azarenka, the 18th seed from Belarus who defeated Italy's Jasmine Paolini 6-3, 7-6 (7/1).
"The next round is going to be exciting for both of us," Azarenka said.
Azarenka and Muguruza have split four career meetings.
"It's going to be a very difficult match. She always plays great here," Muguruza said. "She's one of the best players out there."
Romanian 12th seed Simona Halep, the 2018 French Open and 2019 Wimbledon champion, dispatched Slovakian Kristina Kucova 6-3, 6-1. After an injury-nagged season, it's Halep's deepest US Open run since 2016.
"I feel better. I'm more confident," Halep said. "Before the tournament, I was a little worried with injuries."