Rossetti was born, the son of an Italian patriot and political refugee and an English mother, in England. He was raised in an environment of cultural and political activity that, it has been suggested, was of more import to his learning than his formal education. This latter was constituted by a general education at King's College from 1836 to 1841 and, following drawing lessons at a school in central London at the age of fourteen, some time as a student at the Royal Academy from 1845 onwards. Here he studied painting with William Hollman Hunt and John Everett Millais who, in 1848, would set up the Pre-Raphaelite Brotherhood with Rossetti, Rossetti's younger brother and three other students.

The school's aspirations, in this its first incarnation, was to paint true to nature: a task pursued by way of minute attention to detail and the practice of painting out of doors. Rossetti's principal contribution to the Brotherhood was his insistence on linking poetry and painting, no doubt inspired in part by his earlier and avaricious readings of Keats, Shakespeare, Goethe, Sir Walter Scott, Byron, Edgar Allan Poe and, from 1847 onwards, the works of William Blake.

'The Germ' lasted however for only four issues, all published in 1850. In 1854 Rossetti met and gained an ally in the art critic John Ruskin and, two years later, meetings with Edward Burne-Jones and William Morris set a second phase of the Brotherhood into movement.

In 1860 Rossetti married Elizabeth Siddal, also a writer and a painter, whom he had met ten years earlier in 1850. But, by this time she was an invalid and, after giving birth to a stillborn child, she died just two years later of a laudanum overdose. Rossetti had her interned with the only extent and complete manuscript of his poems, only to have her exhumed seven years later in order to retrieve his work. By this time he had moved to Chelsea where he was a joint tenant with Swinbourne and Meredith. In 1871 he moved again, this time to Kelmscott near Oxford, with William Morris and his wife Jane, the other great love of Rossetti's life whom he painted avidly.

Rossetti collapsed in 1872 after which he never really regained his health. The last decade of his life was spent mostly in a state of semi-invalid hermitry.