While at Oxford, Clough had intended to become a clergyman, but his increasing religious skepticism caused him to leave the university. He became head of University Hall, London, in 1849, and in 1852, at the invitation of Ralph Waldo Emerson, he spent several months lecturing in Massachusetts. He later worked as a government education official and helped his wife's first cousin, Florence Nightingale (Nightingale, Florence), in her philanthropic work. While on a visit to Italy he contracted malaria and died at age 42.

Clough's deeply critical and questioning attitude made him as doubtful of his own powers as he was about the spirit of his age, and he gave his contemporaries the impression of promise unfulfilled, especially since he left the bulk of his verse unpublished. Nonetheless, Clough's Poems (1862) proved so popular that they were reprinted 16 times within 40 years of his death. His best verse has a flavour that is closer to the taste and temper of the 20th century than to the Victorian age, however. Among his works are Bothie of Tober-na-Vuolich (1848) and Amours de Voyage (1858), poems written in classical hexameters and dealing with romantic love, doubt, and social conflict. The long, incomplete poem Dipsychus most fully expresses Clough's doubts about the social and spiritual developments of his era, while his sharpest criticisms of Victorian moral complacency are found in “The Latest Decalogue”:

The Poems of Arthur Hugh Clough (1974), edited by F.L. Mulhauser, is the standard edition of Clough's work.