Mistrangelo was later promoted to archbishop of Florence on 19 June 1899, and served as superior general of the Piarists from 1900 to 1904 as well. Pope Benedict XV created him cardinal-priest of S. Maria degli Angeli in the consistory of 6 December 1915. He was one of the cardinal electors who participated in the 1922 papal conclave, which selected Pope Pius XI.