Returning to Rome in September 1848, he refused to join a papal ministry after the November 15 assassination of Pellegrino Rossi, and spent the next eight years in study and travel.

In the same year he was elected president of the assembly of the Romagna after the rejection of pontifical rule by those provinces, and prepared their annexation to Piedmont.

Both in and out of office he exercised his influence against an Italo-French alliance and for an immediate advance upon Rome, and in 1870 was sent to London and Vienna by the Lanza-Sella Cabinet to organize a league of neutral powers on the outbreak of the Franco-Prussian War.

During his premiership he inaugurated the rapprochement between Italy, Austria and Germany, and reformed the naval and military administration; and before his ouster he was able, as finance minister, to balance the State budget for the first time since 1860.

After the advent of the Left, Minghetti remained for some years in opposition, but towards 1884 joined Depretis in creating the Trasformismo ("Transformation" movement), which united the various liberal factions in the country.