On June 9, 1902, Maffi was appointed Auxiliary Bishop of Ravenna and Titular Bishop of Caesarea in Mauretania by Pope Leo XIII. He received his episcopal consecration on the following June 11 from Lucido Cardinal Parocchi, with Archbishops Felix-Marie de Neckere and Diomede Panici serving as co-consecrators, at the Basilica of Saint Paul Outside the Walls in Rome. Maffi was later advanced to Archbishop of Pisa on June 22, 1903. In addition to his pastoral duties, he was named director and administrator of the Vatican Observatory on November 30, 1904.
Pope Pius X created him Cardinal Priest of S. Crisogono in the consistory of April 15, 1907. Maffi partocione of the cardinals and a chief candidate in the 1914 papal conclave, which selected Pope Benedict XV.
During World War I, Maffi was known as the "War Cardinal" for his support of a fight-to-the-finish policy.
In 1922, he again participated in the conclave, which selected Pope Pius XI. In a 1925 pastoral letter, the Archbishop issued a scathing attack of the Fascist government, which subsequently halted the letter's publication.
A close friend of the Royal Family, in 1930, he presided at the marriage of Crown Prince Umberto of Italy and Princess Marie-Joseph of Belgium. The Cardinal continued to write numerous scientific and astronomical works, the best known of which is Nei cieli. His love for science once provoked Pisa's outrage, when Maffi proposed to erect a statue of Galileo Galilei, the scientist condemned by the Inquisition as a heretic.
Maffi died in Pisa, at age 72. He is buried at the Cathedral of Pisa.