Pickersgill was born into a family of artists and his first teacher was his uncle, the painter W. F. Witherington. In 1840 he was admitted to the Royal Academy Schools and in 1843 won a prize for a drawing of the death of King Lear, an entry for the paintings for the new houses of parliament. One of his paintings, The Burial of Harold, was accepted as a decoration for parliament in 1847.

When he was just 27 he was elected an Associate of the Royal Academy and in 1857 became a full member. Between 1839 and 1875 he showed fifty paintings at the annual Royal Academy Exhibits; most of them were subjects drawn from the works of Spenser, Shakespeare, and Milton. Later in his career, under the influence of the Pre-Raphaelites, he broadened his interests to include finely executed scenes from nature. He also did some work as an illustrator for books, among them the poetry of Milton and Edgar Allen Poe.