The ABC comedy follows a semi-dysfunctional family navigating life in Indiana, starring Patricia Heaton, Neil Flynn and Chris Kattan.
Kaczmarek will play a career-college teacher who doesn't get along with her student Frankie (Heaton), reports The Hollywood Reporter.
Kaczmarek is best known for playing the mum in Fox's Malcolm in the Middle, also starring Bryan Cranston and Frankie Muniz.
Last week, the cast reunited for the first time since the show ended in 2006.
Season four of The Middle will premiere Wednesday, September 26 at 8pm ET on ABC.
Watch a promo of The Middle below: