Thanks to influential friends, including Giovanni Mastai Ferretti (the future Pope Pius IX, also native of Senigallia), he dedicated himself to politics.

When Lodovico Altieri was named cardinal, Bedini gained exposure to the diplomatic atmosphere, and he was subsequently called to Rome as Papal Chamberlain of Gregorius XVI and the Protonotary apostolic.

Giuseppe Garibaldi, who was also living in South America at the time, wrote a famous letter to Bedini in 1847 in which he declared "to offer to Pius IX its sword and the Italian legion for the native land and the church", remembered "the garnishments of our August religion, always new and always immortal" and reminded that "the throne of Peter rests over such foundations that need no aid because the human forces cannot shake them".

Once the Pope had recovered his temporal power, Bedini continued his job of Papal Nuncio and commissioner in the Legations and ambassador to Bologna from 1849 to 1852.

Once he received the archiepiscopal order on 4 July 1852 from cardinal Luigi Lambruschini, he decided to leave for Brazil, but he could not enter the country because of a plague epidemic, so he went to the United States.

He also initiated some plans such as the constitution of the North American College to Rome that with his aid had bought a building on Humility Street on 22 September 1858.

He opened the pastoral visit by going to several of the counties of the diocese and taking care of the sacred places, the monasteries, and especially of the Seminary, where his generosity left considerable debts on his death; in the seminary he improved the instruction (calling Pietro Artemi from Bagnoregio for the rhetorical school), arranged the cleaning of the premises and enlarged the building with the purchase of the Cristofari palace.