The two-time MVP was joined by three-time All-Star Khris Middleton, putting the Bucks' prolific duo in the same line-up for the first time in more than a month.
Antetokounmpo had been out with a sore left knee. Middleton, who hadn't played since December 15 due to a sore right knee, had eight points and four assists.
Milwaukee scored 49 points in the first quarter on Monday night, two shy of the NBA record, and led Detroit by 25 after Antetokounmpo made all six of his shots in eight-plus minutes.
Antetokounmpo didn't keep up his scoring pace the rest of the game, but he didn't have to with teammates such as Bobby Portis scoring 12 of his 18 points in the second quarter.
Portis left the court with a sore right knee early in the fourth after grabbing a 10th rebound for his 29th double-double this season.
Mercifully, the Bucks held the ball and were called for a shot-clock violation in the final seconds when they were three points from matching the most by a NBA team this season.
Milwaukee (30-17) are third in the Eastern Conference standings, while the Pistons (12-37) are bottom.
Isaac missed 211 games since tearing his ACL at Walt Disney World on August 2, 2020. He finished with 10 points, three rebounds and two steals in just under 10 minutes.
Orlando led 55-54 at halftime, then opened up a 13-point lead with the help of three-pointers by Isaac and Gary Harris during a 15-3 run midway through the third quarter.
It was the Magic's third straight win over the Celtics after 10 straight losses.