Rising in the Redhole Spring and Wike Head area of Pikenaze Moor in Derbyshire, the river broadens into the Longdendale Chain of reservoirs in the Peak District National Park. It emerges again in Tintwistle, Derbyshire, at the foot of Bottoms Reservoir dam and passes Melandra Castle in Gamesley, where it is joined by Glossop Brook. The Etherow enters the borough of Tameside at Hollingworth in Greater Manchester, passing into Stockport where it passes through Etherow Country Park. It flows into the River Goyt at Brabyns Park near Marple.
The modern accepted start of the River Mersey is at the confluence of the Tame and Goyt, in central Stockport, 4 miles (6 km) downstream. However, older definitions, and many older maps, place its start at the confluence of the Etherow and Goyt; for example the 1911 Encyclopædia Britannica states "It is formed by the junction of the Goyt and the Etherow a short distance below Marple in Cheshire on the first-named stream." John Stockdale's map published on 12 April 1794 shows the Mersey River extending to at least Mottram, and forming the boundary between Cheshire and Derbyshire.
The upper reaches of the River Etherow pass through peat moorland, inhabited by foxes, voles and an introduced population of mountain hare. Red grouse, ring ouzel, wheatear and golden plover may be seen. Kestrels, merlins and short-eared owls nest here. The reservoirs attract mallards, and also teal, pochard, common sandpipers, black-headed gulls and Canada geese. The woodlands are home to redstart, great spotted woodpecker, and spotted flycatcher. Water rail have been recorded at Etherow Country Park.
Longdendale is a steep-sided V-shaped valley that is glacial in origin. Longdendale is in the Dark Peak, where a thick blanket of peat overlies the Millstone Grit sandstone, formed on a bed of shale through which flows the Etherow. Directly beneath the upper valley lie areas of Carboniferous Millstone Grit, shales and sandstone. It is on the edge of the Peak District Dome, at the southern edge of the Pennine anticline. The Variscan uplift has caused much faulting and Glossopdale was the product of glacial action in the last glaciation period that exploited the weakened rocks. The steep-sided valleys of the cloughs cause significant erosion and deposition. The layers of sandstone, mudstones and shale in the bedrock act as an aquifer to feed the springs. The valley bottoms have a thin deposit of boulder clay. The brooks are fed by the peaty soils of the moors and are, therefore, acidic (pH5.5–7.0).
The Etherow valley was an important trans-Pennine route, and in AD 78 the Romans under Agricola built the fort of Ardotalia (later known as Melandra or Melandra Castle) to defend it. The Mercians settled at Hollingworth about 650 AD. Many placenames of the area date from this period; for example, Mottram and Glossop. At the time of Domesday (1086) the river was firmly established as the boundary between Cheshire and Derbyshire, but the name Edrow or Etherow applied to this upper reach of the Mersey cannot be dated earlier than c.1772.