The Gadfly is set in 1840s Italy, at a time when the country was chafing under Austrian rule. The titular character is a charming, witty writer of pointed political satires who finds himself running with a crowd of revolutionaries. The plot develops as the revolutionaries struggle against the government and as the Gadfly struggles with a mysterious hatred of the Church, and of a certain Cardinal.

The novel, with its complex themes of loyalty, romance, revolution, and struggle against both establishment and religion, was very popular in its day both in its native Ireland and other countries like Russia and China. In Russia, the book was so popular that it became required reading. Since its publication it has also been adapted into film, opera, theater, and ballet, and its popularity spurred Voynich to write sequels and prequels.