The 37-year-old, who had both ankles strapped and required medical attention in her singles match, then combined with Tiafoe but could not overcome Sakkari and Tsitsipas who won the mixed doubles rubber 4-1 1-4 4-2 to seal the tie.
"It's great to be back out in match day, and it's great to be back out here," said Williams, who will be chasing a record-equalling 24th Grand Slam title at the Australian Open next month.
Williams made a several unforced errors early on but overpowered her opponent with 13 aces and 29 winners, claiming two breaks en route to a comfortable win.
"It was my first match back, she played unbelievable. Maria is super young and such a good player. I was making a lot of errors. I was like, 'It's OK, it's your first match and you'll get better'. I just kept trying to think that."
Defeat left six-times winners U.S. at the bottom of the group ahead of Tuesday's meeting with holders Switzerland, who thumped Britain on Sunday.
Roger Federer and Williams, holders of a combined 43 singles Grand Slam titles, will face each other for the first time on Tuesday when they feature in the mixed doubles match alongside partners Belinda Bencic and Tiafoe.
Local media have described the clash as the most anticipated match involving men and women since 1973's "Battle of the Sexes" which saw 39-times major winner Billie Jean King beat former men's world number one Bobby Riggs in an exhibition match.
"It's exciting for both of us and I hope a lot of tennis fans tune in and watch it," Federer said on Sunday.
"I admire everything she's done on and off the court, we're both fierce competitors and we always want to win."
(Reporting by Shrivathsa Sridhar in Bengaluru, editing by Pritha Sarkar)
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