The Esino rises near Monte Penna in Macerata province, near the border with Ancona province, in Le Marche, a region on Italy’s Adriatic coast. The valley, roughly north–south in direction, is delimited on the east and west sides by Apennines sub-ranges, whose highest peaks are respectively Mount Gemmo at 719 metres (2,359 ft) and Mount San Vicino at 1,479 metres (4,852 ft), compared to the 354 metres (1,161 ft) above sea-level of the city centre. It then flows east to pass Esanatoglia before winding north by Matelica. It then crosses into Ancona province near Cerreto d’Esi (in the Verdicchio di Matelica DOC). The river continues north, then winds northeast near Genga. It continues northeast near Serra San Quirico, Maiolati Spontini, Castelplanio, Castelbellino, Jesi, Chiaravalle and Montemarciano before flowing into the Adriatic near Falconara Marittima.

The river, which gives its name to the Esino DOC, also acts a dividing marker for the townships whose vineyards fall within the Verdicchio dei Castelli di Jesi denomination, sparking debates about whether quantifiable terroir-driven differences in style exist between the Esino’s left (north) and right (south) banks.