Santa Maria del Molise is a town and comune located in the Province of Isernia within the Molise region of Italy.
The municipality is situated among several neighboring areas, bordering Carpinone to the north, Roccamandolfi and Castelpizzuto to the south, Macchiagodena to the east, Castelpetroso to the west, and Cantalupo nel Sannio to the south-east.