As a young man, Medhurst studied at Hackney College under George Collison and he worked as a printer and typesetter at the Gloucester Herald and the London Missionary Society (LMS).

[2] En route, he called at Madras where, in a little less than three months, he met Mrs Elizabeth Braune, née Martin (1794–1874), marrying her the day before he sailed to Malacca.

Based upon his studies of Hokkien, in 1831 Medhurst completed his A Dictionary of the Hok-këèn Dialect of the Chinese Language, but printing of all 862 pages of which reached finality only in 1837 after being affected by the end of the British East India Company's trade monopoly in 1834 and for lack of funds.

Medhurst, Elihu Doty, and John Van Nest Talmage developed the Pe̍h-ōe-jī Church Romanization of Southern Min Chinese that was widely used by missionaries.

[6] In the 1840s, a group of four people (Walter Henry Medhurst, John Stronach, Elijah Coleman Bridgman, and William Charles Milne) cooperated to translate the Bible into Chinese.

The initial Gutzlaff translation, completed in 1847 is well known due to its adoption by the revolutionary peasant leader Hong Xiuquan of the Taiping Rebellion as some of the reputed early doctrines of the organization.

He died two days after reaching London, on 24 January 1857[2] and was buried at the Congregationalists' non-denominational Abney Park Cemetery where his white stone obelisk monument can still be seen today.