Misiones borders the departments of Paraguarí and Caazapá to the north, Itapúa to the east, Ñeembucú to the west, and the Corrientes Province of Argentina to the south.

The modern settling of Misiones began with the arrival of Jesuit missionaries to the region in the 17th century and the subsequent establishment of several reductions whose purpose was to both civilize and catechize the indigenous Guaraní peoples.

Some of these reductions, namely San Ignacio Guazú, Santa Maria de Fe and Santiago would become the foundation for subsequent towns in Misiones.

The northern and southern borders of the department are formed by, respectively, the Tebicuary and the Paraná rivers, the latter of which is an important waterway in the region.

The southern part of the department is accessible to the Paraná River, which is navigable by large cargo ships downstream of the Yacyretá Dam near Ayolas.

Part of the historical remains is exposed in Museums with many samples of wooden carvings made by the Indians at the reductions period.