A friend of Charles Macready, Charles Dickens, and Felix Mendelssohn, Clarke became a partner in music publishing with Alfred Novello, whose sister, Mary, he married in 1828. Six years later Clarke began his public lectures on Shakespeare and other dramatists and poets. Those published include Shakespeare Characters; Chiefly Those Subordinate (1863) and Molière Characters (1865). In 1863 he edited George Herbert's poems and in the next 14 years produced new editions of nearly all the English poets.

After his wife had compiled her Shakespeare Concordance (1845), the couple collaborated in an edition of Shakespeare (completed in 1868) and The Shakespeare Key: Unlocking the Treasures of His Style (1879). Clarke was mainly interested in character study, as was his wife, whose Girlhood of Shakespeare's Heroines appeared in 1851–52. The Clarkes left London for Nice in 1856 and in 1861 settled in Genoa, where Clarke remained until his death.