Middleton declared for the 2012 NBA draft after his junior season and was selected by the Detroit Pistons with the 39th overall pick. He saw limited action with the Pistons and spent time with the Fort Wayne Mad Ants of the NBA Development League during his rookie season. Middleton was traded to the Milwaukee Bucks in 2013 and became an immediate contributor to the team. He received his first All-Star selection in 2019 and his second in 2020. In 2021, Middleton helped lead the Bucks to their first NBA championship since 1971. The same summer, he won a gold medal for basketball at the Olympics.