He signed the petition to the Papal conclave, 1846 urging the election of a liberal pope, and was appointed member of the state council summoned to prepare the constitution for the Papal States. With Antonio Montanan and Rodolfo Audinot he founded at Bologna a paper, Il Felsineo. In the first constitutional cabinet of the Papal States, presided over by Cardinal Antonelli, Minghetti held the portfolio of public works, but after Pius IX publicly spoke against the Italian Risorgimento he resigned and joined the Piedmontese army as captain on the general staff.
Returning to Rome in September 1848, he refused to form a cabinet after the assassination of Pellegrino Rossi (15 November), and spent the next eight years in study and travel. Summoned to Paris by Cavour in 1856 to prepare the memorandum on the Romagna provinces for the Paris congress resolving the Crimean War, he was in 1859 appointed by Cavour secretary-general of the Piedmontese Foreign Office. 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.
Appointed Piedmontese minister of the interior, he resigned office shortly after Cavour's death, but was subsequently chosen to be minister of finance by Farini, whom he succeeded as premier in 1863. With the help of Emilio, marquis Visconti-Venosta he concluded (September 15, 1864) the September Convention with France, whereby Napoleon III agreed to evacuate Rome, and Italy to transfer her capital from Turin to Florence. The convention excited violent opposition at Turin, in consequence of which Minghetti was obliged to resign office. He took little part in public life until 1869, when he accepted the portfolio of agriculture in the Menabrea Cabinet.
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. In 1873 he overthrew the Lanza-Sella Cabinet and regained the premiership, which, with the portfolio of finance, he held until the fall of the Right from power on March 18, 1876.
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 ("Tansformation" movement), which consisted in bringing Conservative support to Liberal cabinets. Minghetti, however, drew from it no personal advantage, and died at Rome on the 10th of December 1886 without having returned to power.
His writings include: Della economia pubblica e delle sue attinenze con la morale e col diritto (Bologna, 1859), and La Chiesa e lo Stato (Milan, 1878).