Samuel Greg leased land at a place called Quarrell Hole on the Pownall Fee from Lord Stamford, who attached an unusual condition to the lease: none of the surrounding trees were to be pruned, felled, or lopped. The wood had to stay. Greg accepted the term, partly because he wanted the head of water the River Bollin provided in this quiet wooded gorge, and partly because he wanted easy road access to the Bridgewater Canal and the cotton coming in to Liverpool. The first mill, built in 1784 with his partner John Massey, was a plain four-storey block, 27.5 metres by 8.5 metres, designed for the water frame whose patent had just expired. The American War of Independence had ended and raw cotton was flooding back into the market. By the time Greg retired in 1832, this was the largest cotton spinning business in the United Kingdom.

The first wheel here was a wooden overshot, fed by a long leat from upstream. Peter Ewart built a second wooden wheel in 1801 and dammed the Bollin to deliver water directly. A small iron suspension wheel followed in 1807. Then in 1818, the Great Wheel came. Hewes solved the problem of increasing power without using more water by sinking the wheel pit below river level and routing the tailrace through a kilometre-long tunnel to rejoin the river downstream at Giant's Castle. That gave a 32-foot head onto a 32-foot diameter suspension wheel, 21 feet wide, equivalent in power, an 1835 report calculated, to 120 horses. The Great Wheel ran until 1871, when silt finally choked the mill pool, and was patched back into service until 1904. Two Gilkes water turbines replaced it. Steam engines from Boulton and Watt arrived as backup from 1810, because the Bollin shrank in summer.

The 1784 building ran 2,425 spindles. By 1805 a second wheel and a five-storey extension pushed it to 3,452. Robert Hyde Greg, taking over after his father's death in 1834, introduced power-loom weaving, and weaving sheds went up in 1836 and 1838 to house 305 looms. Quarry Bank's weaving sheds matter to industrial historians because they were two-storey side-lit buildings, not the single-storey saw-toothed sheds that became standard. A weaving shed needed correct light, controlled humidity, and a floor stable enough to take the constant slap of the picking sticks; the Greg solution worked, although later mills generally went the other way. The mill still produces calico today, the same plain cotton cloth it spun in its earliest decades.

Between 1790 and 1841, Quarry Bank ran on the labour of children. They came from workhouses, the Poor Law guardians of Hackney and Chelsea at first and later mostly from Liverpool and the nearby parishes. By 1833 they made up about 20 per cent of the workforce; in the early decades more than half. They lived in the Apprentice House Greg built in 1790, up to 90 at a time, supervised by a superintendent. Their hours were 12 a day, six days a week, according to documents from 1794, with play allowed only on Sunday afternoons. Fingers were sometimes severed by the machines. Peter Holland, employed as mill doctor and the first occupational physician on record in Britain, looked after them. Their diet, Professor Hannah Barker's research has shown, was relatively good for the period. Education was limited, more so for girls than for boys until the 1830s. Corporal punishment was avoided, but bad behaviour was punished by overtime, by threats to shave girls' heads, or by being locked in a room on a porridge-only diet for days. Children at Quarry Bank were treated, in one comparative study, better than average. They were not treated well.

The Gregs were Unitarians, they provided medical care for all workers, and Hannah Greg pushed her husband toward what was for the period a comparatively humane labour policy. They were also part of a wider family commerce that included plantations worked by enslaved people in Dominica and St Vincent. Samuel's brother Thomas inherited the Hillsborough plantation in Dominica; the same Greg family records list 71 enslaved men and 68 enslaved women on one estate in 1818. Samuel Greg did not finance Quarry Bank directly from Caribbean earnings, but his brothers did own plantations, and the cotton itself was very largely grown by enslaved hands in the American South. The National Trust now tells this part of the story at the site. The 1842 Plug Plot riots reached the mill on 10 August that year, when striking workers from across Lancashire and Cheshire tried to draw the plugs from the boilers and stop production. The mill was attacked. It survived. So did the system, until the 1847 Factory Act finally curtailed the worst of the hours.