It rises near the Futa Pass, at 1,222 metres (4,009 ft) of elevation, in the Apennine ridges facing the plateau of Firenzuola in the Metropolitan City of Florence.

Beyond Firenzuola, it flows northeast through the province of Bologna near Castel del Rio, where it is crossed by a famous medieval bridge, the Ponte degli Alidosi.

It then flows past Fontanelice, Borgo Tossignano, Casalfiumanese, and, once in the Pianura Padana (the Po River's valley), Imola.

It is probable that, in ancient times, the river flowed eastward from Bagnacavallo, as confirmed be the existence of a frazione of Ravenna called Santerno.

In those days, after Imola, the river divided into two branches, one moving northeast toward Ravenna, the other continuing northward to join the Po.