It rises in the Monti della Meta, flows south-west for about 40 kilometres (25 mi) and joins the Liri near San Giovanni Incarico.

In a series of rapids and cascades, it descends the Valle di Comino, passing through Picinisco, Atina— where it receives the waters of the little Mollarino— Casalattico and Casalvieri.

Below Casalvieri it passes for 15 km through a deep gorge in the foothills of Monte Cairo at the end of which it reaches the Liri, near Roccasecca.

The origin of the name is obscure, perhaps to be associated with the goddess Mefitis, worshipped in a sanctuary uncovered in 1958 at the place called Capodaqua, right below the source.

Other toponyms from the same root include the locality Melfi a Pontecorvo, also near the Liri, seat of an ancient cult of John the Baptist; the city of Melfi and Molfetta, anciently Melficta; Melpum in the central Paduan plain, perhaps also Amalfi; in Lucania the hydronym Melpes is found.