While apprenticed to a cabinet-maker, Wylie picked up a Chinese grammar book written in Latin (the Notitia linguae sinicae by Joseph Henri Marie de Prémare).

After having mastered Latin, he went on to make such good progress in Chinese that, in 1846, James Legge engaged him to superintend the London Missionary Society's press in Shanghai.

[1][2] He made several journeys into the interior, notably in 1858 with Lord Elgin on a British Navy gunboat up the Yangtze and to Nanjing, where he served as one member of a delegation of three to meet with officials of the Taiping, and in 1868 with Griffith John to the capital of Sichuan and the source of the Han.

He completed the distribution of one million Chinese New Testaments provided by the British and Foreign Bible Society's special fund of 1855.

Blind and bed-ridden, he died at his home, 18 Christchurch Road, Hampstead on 6 February 1887 and was buried on the western side of Highgate Cemetery (plot no:15429).