Smetham worked in a number of genres: landscapes, portraits, and literary and religious themes. He began his studies at the Royal Academy in 1843, but mental illness that fully manifested itself in the mid-1870s plagued his later career, and after 1869 he no longer exhibited at the Royal Academy.
Smetham was also a critic and essayist. His article on William Blake in the Quarterly Review (1868) is one of the first evaluations to suggest the importance of Blake as an artist.