Historically part of Cheshire, it lies in the valley of Longdendale, on the border with Derbyshire and close to the Peak District neighbouring Broadbottom and Hattersley. Mottram in Longdendale Parish was one of the eight ancient parishes of the Macclesfield Hundred of Cheshire. The larger Mottram parish was incorporated into Longdendale in 1936, remaining part of Cheshire, then incorporated into Tameside, as part of the provisions of the Local Government Act 1972 in 1974. Even as late as 1991, the town has the preferred name of Mottram in Longdendale.
In 1795, Aikin in his book, Forty Miles around Manchester, wrote
In the 18th century the River Etherow was known as the Mersey. The River Tame has been a border from the earliest times between the Anglo-Saxon kingdoms of Northumbria and Mercia. The ancient parish was the most northerly in Cheshire. Mottram came to prominence as a transport hub. It lies on two pack horse routes used to carry salt from Cheshire to South Yorkshire over the Pennines and carry lime for soil improvement from Chapel-en-le-Frith. It was on the Manchester to Sheffield stage coach route, and had a flyer service to Manchester. Before the Industrial Revolution Mottram and Ashton had been the most significant towns in the area, the manor and manorial court house were in Mottram, but other towns eclipsed Mottram in size and importance. Mottram was active in the early stages of industrialisation, and there were significant cotton spinning mills in Wedneshough Green and the Treacle Street areas of Mottram Moor, and printing and dyeing works on the Etherow at Broadbottom which until recently was part of the parish.
The smaller early mills in Mottram became uneconomic and harder to run. Stalling industrialisation led to social conflict and hunger during 1812 Luddite riots that led to the smashing of labour-reducing machines. The Luddites secretly drilled on Wedneshough Green. In 1842 local Chartists met on the green, and planned the closure of Stalybridge factories in the Plug Riots. By 1860 the population had peaked. The 1844 railway passed through the valley with stops at Hattersley and Broadbottom in the parish but not at the Mottram township.
A Polish pilot, Josef Gawkowski, was killed on 19 July 1942 when his aircraft crashed near Mottram on a training flight from RAF Newton in Nottinghamshire. A memorial plaque commemorating him is located in Mottram Cemetery.