The Gadfly begins with the sheltered youth of Arthur Burton. He is devoted to his mother, an Italian widow who dies when he is sixteen; his guardian and mentor, the priest Montanelli, who is also secretly his biological father; and his sweetheart, Gemma, his partner in amateur political activities. Gemma, like the young Ethel Boole, is a passionate British idealist who always dresses in black. The idyll ends when Arthur is tricked into betraying his political secrets to a priest who is also a spy; at the same time he discovers his true parentage, and he loses all trust in Montanelli and the Catholic Church. Feigning suicide, Arthur sails for South America; as Felice Rivarez, he is mutilated, lamed, and disgraced. Years later he returns to Italy as the Gadfly to serve as satirist for the Young Italy movement against Austrian tyranny. Montanelli, now a cardinal, is forced to condemn him to death but tries secretly to rescue him. The Gadfly reveals his identity but refuses to be saved unless Montanelli admits that he and his church are frauds. Montanelli refuses to join the Gadfly and his revolutionary struggle, while the Gadfly refuses to accept mercy from his hypocritical father. After writing a gentle love letter to Gemma, the Gadfly dies, cheerfully mocking the incompetent firing squad. Montanelli, too, dies after declaiming his guilt and God's.

Ethel Lilian Voynich, née Boole (May 11, 1864–July 27, 1960) was a novelist and musician, and a supporter of several revolutionary causes. Her father was the famous mathematician George Boole. Her mother was feminist philosopher Mary Everest, niece of George Everest and an author for the early-20th-century periodical Crank. In 1893 she married Wilfrid Michael Voynich, revolutionary, antiquarian and bibliophile, the eponym of the Voynich manuscript.