Lillard scored 15 points in the third quarter and finished with six 3-pointers, nine rebounds and five assists.
Antetokounmpo shot 8 for 11 from the floor and had a game-high 14 rebounds as Milwaukee got double-figure scoring from six players.
Taurean Prince and Bobby Portis scored 16 points apiece for the Bucks, how had 16 3-pointers.
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Tyrese Maxey scored 25 points and Andre Drummond had 13 points and 11 rebounds for Philadelphia, which was without injured stars Joel Embiid and Paul George, who are sidelined due to knee injuries.
FAN REACTIONS
Many expressed their disappointment after the 76ers lost to the Bucks Wednesday night.
"I wish the Sixers did better but they still tried their hardest. So go Sixers," said Norhi Goodman from Lawnside, New Jersey.
Fans said it was made even worse when officials announced that Embiid and George would not be on the court for the team's first game of the season.
"I was excited up until I found out Embiid is not playing. George I knew wasn't going to play because he got hurt, but when I bought these tickets two months ago, we spent top dollar," noted Sidney Steinberg from Williamstown, New Jersey.
Despite a tough loss, fans are hopeful that the team will turn things around soon.
"We got to keep our heads up -- long season ahead of us. We started up but we going to bounce right back once we get Embiid and Paul George out there," said Kevin Mcnicholas from Paterson, New Jersey.
TAKEAWAYS
Bucks: Lillard and Brook Lopez ran the pick and roll frequently against Philly. The picks were extended out beyond the 3-point line. Several of Lopez's picks were set at or near half court, allowing Lillard to have a combination of time and space to create offense.
76ers: Guerschon Yabusele played his first game in the NBA since 2019. After playing internationally for five seasons, Yabusele provided the 76ers with 10 points, four rebounds, three assists and three steals in 25 minutes.
KEY MOMENT
Milwaukee used a 25-12 run in a six-minute span of the second quarter to pull away. Bobby Portis was a key figure for the Bucks during that time. On consecutive plays, Portis blocked a shot, grabbed a defensive rebound, assisted Taurean Prince on a layup, picked up a steal and scored on a running layup.
KEY STAT
Lillard and Antetokounmpo became the first pair of Bucks teammates to register at least 25 points, five rebounds and five assists in a season opener.
UP NEXT
The Bucks have their home opener against Chicago on Friday. On the same night, Philadelphia travels to Toronto.
The Associated Press contributed to this report.