Polidori was the eldest son of an Italian political scholar and a British governess. He had three brothers and four sisters, one of whom, Frances Polidori, married Gabriele Rossetti, and was mother to Dante Gabriel Rossetti, William Michael Rossetti, Christina Rossetti and Maria Francesca Rossetti.
After graduating from the University of Edinburgh with a medical degree, he became Byron’s travelling companion and personal physician in Switzerland. Hot tempered and arrogant, he would often infuriate his employer; ‘Pray’, he asked Byron one day, ‘what is there excepting writing poetry that I cannot do better than you?’ ‘First’, replied Byron, ‘I can hit with a pistol the keyhole of that door – Secondly, I can swim across that river to yonder point – and thirdly, I can give you a d___d good thrashing.’ Polidori was dismissed by Byron in September 1816 and travelled in Italy before returning to England.
While resident in London, Polidori began a new career in the law, but in August 1821 committed suicide over a gambling debt, aged just 25.