Antetokounmpo, the league MVP in 2019 and 2020, had 21 points, 13 rebounds and eight assists to lead the Bucks that overcame the loss of their second-leading scorer, Khris Middleton, still recovering from left wrist surgery.
For the Sixers, James Harden shined with 31 points, eight rebounds and nine assists, but Cameroonian centre Joel Embiid was a wreck with just 15 points (6 of 21 from the field) and none of them in the second half.
The Sixers, who lost in their opener to the Boston Celtics, drew some boos from their fans at the Wells Fargo Center during a game in which they trailed by 13 points (80-67) in the final quarter.
The home side responded with James Harden leading a 13-0 run to tie the Sixers at 80-all with six minutes to play.
But the Bucks continued to exploit Antetokounmpo's authority in the paint and the success of centre Brook Lopez from outside (17 points with four three-pointers).
The Sixers took their first lead since the first minute of the game, but Wesley Matthews hit a three-pointer with 24 seconds left and Harden missed a forced layup under great defence from Jrue Holiday to put the game away for the visitors.
"They are a great team. We did a really good job of keeping our composure and trusting each other," Antetokounmpo said.
In the other game of the day, the Los Angeles Lakers suffered their second loss in an official game against their neighbours the Clippers (97-103).
