The river's source lies in Yelninsky District, east-southeast from the city of Smolensk and not far from Yelnya in a forest near the village of Naleti.

The Desna then flows south through a low and swampy valley toward the city of Bryansk, where the river's right bank rises.

After its confluence with the Seym near the Russian-Ukrainian border, the river then widens, splitting into numerous smaller branches.

Its right bank declines again near the city of Chernihiv, and again near one of its tributaries, the Oster, where the Desna continues its course through a low, muddy plain until it finally reaches its mouth near Kyiv at the Dnieper River.

The most significant (length more than 100 km) are, from source to mouth: The Svensky Monastery is located at the confluence of the Desna and the Sven River.