His father, Vincenzo, a tenant farmer on a large scale at La Manziana, had taken part in the defence of the Roman Republic under Giuseppe Garibaldi in 1849, was exiled by Pius IX, and re-entered Rome in 1870 through the breach of Porta Pia.

[2][4] On the resignation of Giolitti in March 1905, Tittoni became interim premier for a few days and remained in Alessandro Fortis's cabinet as foreign minister.

His proposal to reduce the duty on Spanish wines in connection with an Italo-Spanish commercial treaty aroused a storm of indignation among the agricultural classes and caused the fall of the cabinet on 24 December 1905, and although Fortis composed a new administration, Tittoni did not enter it.

After the Bosnian crisis and the annexation of Bosnia-Herzegovina by Austria-Hungary, his imprudently worded speech at Carate created the illusion that Italy was to be compensated, perhaps by the cession of the Trentino, and the disappointment when nothing of the kind materialized greatly weakened his prestige.

[2] As foreign minister, Tittoni prudently advanced Italian claims on Tripolitania, at the time part of the Ottoman Empire, without resorting to outright threats of annexation.

[6][7] On 24 October 1909, Tittoni and the Russian diplomat Aleksandr Izvolsky exchanged diplomatic notes on an informal agreement, known as the Racconigi Bargain, for Russia and Italy to support each other's interests in the Balkans and in the Ottoman Empire, at the Italian city of Racconigi, Tsar Nicholas II of Russia was hosted by King Victor Emmanuel III.

On the fall of the Orlando Cabinet in June 1919, the new Premier, Francesco Saverio Nitti, chose Tittoni as foreign minister and first delegate at the Paris Peace Conference.

[4][9] After the March on Rome, Tittoni supported Mussolini's government and later became the first president of Royal Academy of Italy (28 October 1929 – 16 September 1930), the most important cultural institution of the fascist dictatorship.