It rises in the Abruzzese central Apennines of Samnium near Castel San Vincenzo (province of Isernia, Molise) and flows southeast as far as its junction with the Calore Irpino near Caiazzo and runs south as far as Venafro, and then turns southwest, past Capua, to enter the Tyrrhenian Sea in Castel Volturno, northwest of Naples.

The united stream now flows west-southwest past Capua, where the Via Appia and Latina joined just to the north of the bridge over it, and so through the Campanian plain, with many windings, into the sea.

The river has always had a considerable military importance, and the colony of Volturnum (no doubt preceded by an older, possibly even Etruscan, port of Capua) was founded in 194 BC at its mouth on the south bank by the Romans; it is now about one mile inland.

Following the invasion of southern Italy by revolutionary forces led by Giuseppe Garibaldi in 1860, Francis II of the Two Sicilies fled from Naples and took up a defensive position on the south bank of the Volturno, near S. Maria di Capua Vetere.

The Piedmontese troops and those of Garibaldi inflicted on the Neapolitan forces at the battle of the Volturno, on 1 and 2 October, a defeat which led to the fall of Capua.