Sewell was born on 30 March 1820 in Great Yarmouth, Norfolk, into a devout Quaker family. Her father was Isaac Phillip Sewell (1793–1879), and her mother, Mary Wright Sewell (1798–1884), was a successful author of children’s books. She had one sibling, a younger brother named Philip. The children were largely educated at home by their mother due to a lack of money for schooling.

In 1822, Isaac’s business, a small shop, failed and the family moved to Dalston, London. Life was difficult for the family, and Isaac and Mary frequently sent Philip and Anna to stay with Mary’s parents in Buxton.

In 1832, when she was twelve, the family moved to Stoke Newington and Sewell attended school for the first time. At fourteen, Sewell slipped and severely injured her ankles. For the rest of her life she could not stand without a crutch or walk for any length of time. For greater mobility, she frequently used horse-drawn carriages, which contributed to her love of horses and concern for the humane treatment of animals.

In 1836, Sewell’s father took a job in Brighton, in the hope that the climate there would help to cure her. At about the same time, both Sewell and her mother left the Society of Friends to join the Church of England, though both remained active in evangelical circles. Her mother expressed her religious faith most noticeably by authoring a series of evangelical children’s books, which Sewell helped to edit, though all the Sewells, and Mary Sewell’s family, the Wrights, engaged in many other good works. Sewell assisted her mother, for example, to establish a working men’s club, and worked with her on temperance and abolitionist campaigns.

In 1845, the family moved to Lancing, and Sewell’s health began to deteriorate. She travelled to Europe the following year to seek treatments. On her return, the family continued to relocate – to Wick in 1858, and to Bath in 1864.

In 1866, Philip’s wife died, leaving him with seven young children to care for, and the following year the Sewells moved to Old Catton, a village outside the city of Norwich in Norfolk, to support him.

Sewell sold the novel to Norwich publisher Jarrolds on 24 November 1877, when she was 57 years old. She received a single payment of £40 (£3,456 or US$4,630 in 2017) and the book was published the same year.

After the publication of her only novel, Sewell fell seriously ill. Sewell was in extreme pain and completely bedridden for the following months, and she died on 25 April 1878 aged 58 of hepatitis or tuberculosis, only five months after the publication of Black Beauty. She was buried on 30 April 1878 at Quaker burial-ground in Lamas near Buxton, Norfolk, not far from Norwich.

There is an Anna Sewell memorial fountain and horse trough outside the public library in Ansonia, Connecticut, in the United States of America. It was donated by Caroline Phelps Stokes, a philanthropist known for her work supporting animal welfare, in 1892.

A memorial fountain to Sewell is located at the junction of Constitution Hill and St. Clement’s Hill in Norwich, which also marks the entrance to Sewell Park. The fountain was placed in 1917 by Sewell’s niece Ada Sewell.

On 1 September 1984 the graveyard at Lamas was bulldozed by contractors under the direction of Mrs Wendy Forsey without prior warning or permission. Tombstones, graves and cypress trees were removed and dumped at the edge of the burial ground. The act was condemned by locals and Council Chairman John Perkins who said “I know the land belongs to a private person but I would almost say it was as bad as vandalism. I know Quaker ground is not consecrated, but for anybody to just pull down gravestones of any Quaker, whether it’s Anna Sewell or not, well, I think it’s despicable”. The gravestones of Anna, her parents and maternal grandparents were subsequently placed in a flint-and-brick wall outside the old Lammas Quaker meeting house.

In 2020, a street in Chichester, West Sussex, was named in Sewell’s honour on the Keepers Green estate.