Most of the river's catchment lies on the western flank of the Pennines. The named river starts as compensation flow (that is, a guaranteed minimum discharge) from Readycon Dean Reservoir in the moors above Denshaw. The source is a little further north, just over the county border in West Yorkshire, close to the Pennine Way. The highest point of the catchment is Greater Manchester's highest point at Black Chew Head.
The river flows generally south through Delph, Uppermill, Mossley, Stalybridge, Ashton-under-Lyne, Dukinfield, Haughton Green, Denton and Hyde. The Division Bridge (which spans the river at Mossley), marks the meeting point of the traditional boundaries of Lancashire, Yorkshire and Cheshire. The section through Stalybridge was once mooted as a diversion route for the restoration of the Huddersfield Narrow Canal. For all its remaining course after the Division Bridge, the river marks much of the historical boundary dividing Cheshire and Lancashire, before confluence with the River Goyt to form the River Mersey at Stockport. The 19th century industrial concentrations in the above-named urban areas resulted in the Tame being a much polluted waterway. As well as industrial pollution from the dyes and bleaches used in textile mills, effluent from specialised paper-making , engineering effluents, including base metal washings from battery manufacture, phenols from the huge coal-gas plant in Denton, rain-wash from roads and abandoned coal spoil heaps there was also the sewage effluent from the surrounding population. Up to two-thirds of the river's flow at its confluence with the Goyt had passed through a sewage works. The anti-pollution efforts of the last thirty years of the 20th century have resulted in the positive fauna distributions listed below.
The Centre for Ecology and Hydrology measures the flow at two points for the National River Flow Archive, at Portwood weir (Stockport) and at Broomstairs weir (Denton). Portwood weir is 1¼ miles above the confluence with the Mersey and contains the great majority of the final flow (with the exception of waste water from a concrete facility).