Mazzella entered the ecclesiastical seminary of Benevento when about eleven years of age, completed his classical, philosophical, and theological studies before his twenty-fourth year, and was ordained priest in September 1855, a dispensation as he was under canonical age having been granted by Pope Pius IX.

[2] For two years after his ordination he remained at Vitulano, attending to the duties of canon in the parish church, a position he held from his family.

[3] After spending a year in the novitiate, he was sent to teach philosophy first, at the Seminary of Andria, in Apulia and then at the College of Cosenza, in Calabria.

Mazzella served at various times as prefect of a number of Curial Congregations, and as Cardinal-Protector of several religious institutes.

Mazzella was conservative and an Ultramontanist and likely contributed to the drafting of Testem benevolentiae nostrae, Pope Leo's 1899 letter to James Cardinal Gibbons cautioning him about the dangers of Americanism.