Clough, whose father was a cotton merchant, spent many of her early years in Charleston, S.C. She returned with her family to England in 1836 and began teaching a few years later. In 1852 she opened a school at Ambleside, Westmorland. A strong supporter of the movement for the higher education of women, she worked with Emily Davies, Frances Mary Buss, Henry Sidgwick, and other educators. She played a prominent part in founding the North of England Council for Promoting the Higher Education of Women and was its secretary (1867–70) and president (1873–74). She persuaded James Stuart, the founder of university extension programs, to give lecture courses in the North of England, which led to the admission of women to the colleges at Manchester and Newcastle. When Henry Sidgwick planned a house for women students at Cambridge, Clough was selected as principal, a position she held until her death. The house was started in 1871 with five students, and its success led to the building of Newnham Hall (1875) and the foundation of Newnham College (1880).