The river rises close to the source of the River Goyt just to the south west of Buxton, on Axe Edge Moor in Derbyshire (close to Staffordshire's county top on Cheeks Hill). From the moor, it flowing southwest, it forms the border between Cheshire and Derbyshire for a short while and then reaches Three Shire Heads, where the three counties meet, at Panniers' Pool Bridge.
Below Three Shire Heads, the Dane marks the border of Cheshire with Staffordshire for around 10 miles before definitively entering Cheshire and flowing west through Congleton. The Dane Valley Way footpath tracks much of this course, through Danebridge and on toward Congleton.
Below Congleton the Dane passes Holmes Chapel, then passes just to the north of Middlewich. It accepts the waters of the River Croco near the site of the old Roman fort in Harbutt's Field, and then the River Wheelock near the aqueduct carrying the Trent and Mersey Canal. It runs five miles further north to Northwich where it flows into the River Weaver.