[1][2] Mezzofanti lost his university position for refusing to take the oath of allegiance required by the Cisalpine Republic, which governed Bologna at the time.

Mezzofanti held this post until he went to Rome in 1831 as a member of the Congregation for the Evangelization of Peoples (Congregatio de Propaganda Fide), the Catholic Church's governing body for missionary activities.

In 1833, he succeeded Angelo Mai as Custodian-in-Chief of the Vatican Library, and in 1838 was made cardinal of Sant'Onofrio and director of studies in the Congregation for the Evangelization of Peoples.

[9] It has been suggested that some reports of Mezzofanti's abilities may have had a hagiographical character, comparable to claims that certain Catholic saints could perform miracles such as levitation or bilocation.

[11] Linguists have also pointed out that lay people (i.e. non-linguists) frequently misunderstand what true language proficiency entails, or underestimate the difficulty in acquiring and maintaining it, and thus caution against reading contemporary accounts of Mezzofanti's abilities uncritically.

Additionally, Mezzofanti's duties as a cardinal who engaged with foreign dignitaries would have largely involved the use of a small set of canned phrases, the use of which do not necessarily indicate actual linguistic fluency.