He was born at Tenby in Pembrokeshire. He studied at the Slade School of Art in London and even before his graduation had proven to be the most talented draughtsman of his generation. His sister, Gwen John, was an equally talented artist.
Although well-known early in the century for his drawings and etchings, the bulk of John's later work consisted of portraits, some of the best of which were of his two wives and his children. He was known for the psychological insight in his portraits, many of which were considered "cruel" in the truth of the depiction. Lord Leverhulme was so upset with his portrait that he cut out the head and returned the rest of the picture. John painted many distinguished contemporaries, including Thomas Hardy, W.B. Yeats, George Bernard Shaw, the cellist Guilhermina Suggia, the Marchesa Casati and Elizabeth Bibesco. Perhaps his most famous portrait is of his fellow-countryman, Dylan Thomas.
He is said to have been the model for the painter depicted in Joyce Carey's novel The Horse's Mouth, which was also filmed with Alec Guinness in the part.
By his first wife, Ida Nettleship (1877-1907), he had five children, and by his mistress Dorothy "Dorelia" McNeill, who later became his second wife, he had two children. By Ian Fleming's mother, Evelyn St. Croix Rose Fleming, he had a daughter, Amaryllis Fleming (1925-1999), a noted cellist. Another close female friend was Lady Ottoline Morrell. He was noted for his bohemian lifestyle is said to have had numerous affairs with both notable and obscure women.