The stream is formed at the foot of Monte Barifreddo in the Cottian Alps and initially runs north-northwest through the Parco Naturale della Val Troncea. The course then follows a semi-circular path through the Val Chisone passing to the east, the north and then to the west of Monte Albergian. Near Perosa Argentina it receives the waters of the Germanasca, its main tributary. The Chisone enters the Pellice some to the east of Pinerolo, the most important of the settlements on its course.