Cornforth met Rossetti in 1856, and became his model and mistress in the absence of Elizabeth Siddal whom Rossetti married in 1860, under the impression that she was dying. Many biographers presumed Siddal disliked Cornforth, but there is no proof that Siddal even knew of her existence. Cornforth's first role was as to model the head of the principal figure in the painting Found, which she later described, saying he "put my head against the wall and drew it for the head of the calf picture".
Three months after Rossetti's wedding Cornforth married mechanic Timothy Hughes, but the relationship was short-lived. The couple separated. It is not known for certain when she adopted the name "Fanny Cornforth", but Cornforth was the name of her first husband's stepfather, which she took as her surname.
After Siddal's death in 1862, Cornforth moved into the widowed Rossetti's home as his housekeeper. The affair between them lasted until Rossetti's death. For much of the time Rossetti was engaged in an off-and-on relationship with Jane Morris who was married to his colleague, William Morris. Their relationship was not made public but his relationship with Cornforth was.
Cornforth came from the lower/rural working class of English society. Her coarse accent and lack of education shocked Rossetti's friends and family. Rossetti's brother William Michael Rossetti praised her beauty, but said "she had no charm of breeding, education, or intellect". Many never accepted her and pressured Rossetti to end the affair. Over the course of their relationship, Cornforth gained weight. Much has been made of this by biographers, but the growing girths of both Rossetti and Cornforth was a mutual joke. His pet name for her was "My Dear Elephant" and she called him "Rhino". When they were apart, he drew cartoons of elephants and sent them to her, often signing himself "Old Rhinocerous".
After Rossetti's health started to decline seriously, his family became more directly involved in his life. Cornforth was forced to leave Rossetti's house in 1877. Rossetti paid for a house for her nearby, writing to her "You are the only person whom it is my duty to provide for, and you may be sure I should do my utmost as long as there was a breath in my body or a penny in my purse." He gave her several of his paintings, ensuring that her legal ownership was documented.
Her estranged husband had died in 1872. While separated from Rossetti, she became involved with John Schott, a publican from a family of actors. Schott divorced his first wife, who was already living in a bigamous marriage with another man, to marry her. He married Fanny almost immediately after the divorce, in November 1879. The couple ran the Rose tavern in Jermyn Street, Westminster, London. Cornforth nevertheless repeatedly returned to Rossetti to nurse him, accompanying him to Cumbria in 1881. After Rossetti's death, she and her husband opened a Rossetti gallery in 1883 to sell some of the works she owned.