Main-Spessart is a Landkreis (district) in the northwest of Bavaria, Germany.

It is located in Lower Franconia and derives its name from the river Main and the wooded hills of the Spessart.

The river Main forms a large horse-shoe bend in the district, entering in the southeast near Thüngersheim and leaving to the southwest near Hasloch.

The Spessart hills cover most of the area of the district west and north of the Main.

Although Lohr is the largest town, the seat of the administration is located in Karlstadt.