Antetokounmpo also grabbed 12 rebounds and contributed five assists as the Cavs failed to fire.
Antetokounmpo, 21, also grabbed 12 rebounds and contributed five assists as a Cavs side featuring both James and Kyrie Irving failed to fire.
Greek international Antetokounmpo was ably supported by Jabari Parker (18 points) and Michael Beasley (17) as the Bucks scored a win which improves their season to 8-8.
The Cavs loss saw the champions fall to 13-3 for the season. James finished with 22 points to lead the scoring for the Cavs, ahead of Irving with 20 points at the BMO Harris Bradley Center.
But the star of the night was Antetokounmpo, who became one of the highest paid players in the NBA earlier this year when he inked a $100 million four-year deal worth around $25 million a season.
Last season the giant forward averaged 16.9 points, 7.7 rebounds. 4.3 assists and 1.4 blocks in 80 games. So far this season Antetokounmpo is averaging 22 points per game, suggesting the Bucks were wise to invest in the 6ft 11in son of Nigerian immigrants who was born in Athens in 1994.
"We were moving the ball and we didn't stop moving the ball," Antetokounmpo said. "Our pace was great, we rebounded the ball well and we moved the ball in the offensive end."
James said the Cavs have been caught napping.
"We let our guard down a little bit," James said. "They pushed up the tempo and we didn't get stops. I came out of the game when we were up 10 and we let them go on a quick run to end the quarter. From that point on they got into a rhythm and they're a rhythm team."
The Bucks' upset win was the biggest shock of the day as various in-form teams ended up losing to unheralded opposition.
San Antonio's nine-game winning streak came to an abrupt halt when the Western Conference giants crashed to a 95-83 defeat against the Orlando Magic.
Serge Ibaka scored 18 points while Nikola Vucevic added 12 points and 10 rebounds as the Magic silenced the Spurs fans at the AT&T Center.
The victory ended a four-game losing streak for Orlando, who improved to 7-11 with the win. San Antonio slipped to 14-4 after the loss.
The Spurs saw any chance of victory slip away in the fourth quarter when they missed seven straight shots in a scoreless four minute, 10 second spell in the fourth quarter.
It was Orlando's first win over San Antonio in 11 meetings dating back to 2010.
Spurs star Kawhi Leonard led the scoring for the home side with 21 points with LaMarcus Aldridge adding 16 points and Manu Ginobili chipping in with 13.
The Los Angeles Clippers fell to 14-5 against the Brooklyn Nets in New York, with the underdogs improving their record to 5-12 after a wild 127-122 win in double overtime.
Sean Kilpatrick was the hero for the Nets, finishing with a career-high 38 points -- 31 of them coming after the third quarter -- as Brooklyn reeled in the Clippers who at one stage had led by 18 points.
A stormy contest saw Clippers coach Doc Rivers ejected after an angry outburst at referee crew chief Ken Mauer. Rivers needed to be restrained by players before leaving the court in disgust.
In New Orleans, Anthony Davis maintained his prolific start to the season with 41 points as the Pelicans dismantled the Los Angeles Lakers 105-88.
Davis also plucked 16 rebounds as the Pelicans snapped a two-game losing streak with their fifth straight home victory at the Smoothie King Center.
The win saw the Pelicans improve to 7-12 while the Lakers fell to 9-10.
Davis's tally marked the seventh time this season he has finished with at least 35 points and 10 rebounds in a game.
The 23-year-old is now averaging just under 32 points per game for the season, and leads the league's scoring standings from Russell Westbrook (30.9 points per game).