Born of Mount Paflagone, a buttress of Mount Cervialto, in the heart of the Picentini Mountains Regional Park in Irpinia, the Sele River, at the beginning of its course, feeds the Apulian Aqueduct (Acquedotto Pugliese) in Caposele.

A small portion of the water from the Irpinia source continues its natural course south for 64 kilometers, making it the third longest river in Campania. Its numerous tributaries on both sides contribute to the Sele's flow to its mouth. At Campagna, in the Valley that gives it its name, it receives the waters of the Tenza, while at Contursi Terme it receives those of its main tributary, the Tanagro, coming from the Vallo di Diano. It also flows through the Persano oasis, where it forms an artificial lake following the construction of a dam in 1932, and then reaches Eboli, in the vast and fertile Sele Plain, where it receives the waters of other tributaries.

Near Paestum, having also received water from the Calore Lucano, the river crosses the archaeological area with the remains of the Heraion, the sanctuary of Hera Argive built in the 6th century BC right near the ancient outlet to the sea. It is at least a kilometer from the current estuary where the river flows into the Tyrrhenian Sea in the Gulf of Salerno.