The 25-year-old who led the Milwaukee Bucks a year ago with 18.2 points per game, tore his hamstring on Wednesday.
Swing man Middleton will need surgery and will miss at least six months.
“We’re obviously disappointed for Khris and our team, but injuries are an unfortunate part of the game,” Bucks general manager John Hammond said in a statement.
“We’ll rely on our overall roster depth to help us while Khris is out for a significant period of the season.”
The Bucks’ preseason schedule begins on October 3 against the Chicago Bulls with the regular-season opener later that month at the Bradley Center against the Charlotte Hornets.