Having displayed a considerable knowledge in Oriental affairs, he was sent to the Pontifical Academy of Ecclesiastical Nobles as preparation for service in the Roman Curia.

In 1880 he was named Secretary of the Congregation for the Propagation of the Faith, the Vatican office which deals with areas of the world in which there is no regularly constituted hierarchy of bishops.

[1] In the consistory of 14 March 1887, Pope Leo XIII created Rampolla del Tindaro a Cardinal-Priest, and on 26 May assigned him the titular church of Santa Cecilia in Trastevere.

As Secretary of State, Cardinal Rampolla supported the Austrian Christian Social Party, led by Karl Lueger, sometime mayor of Vienna (1897–1910).

[4] Rampolla expressed his opinion that the French people were obligated to support Prime Minister Jules Méline at the height of the Dreyfus Affair.

His candidacy gained momentum until the last moment when the Austrian Emperor Francis Joseph I imposed the veto jus exclusivae during the conclave.

However, Merry del Val later told Ludwig von Pastor that he thought Rampolla was unlikely to win since a majority of the cardinals wanted a more conservative direction following the relatively liberal pontificate of Pope Leo XIII, as did he himself.

[4][e] While some prelates formally protested this intrusion after voting had been in progress, the Ultramontanist Cardinals readily recognized the existing legal right of the emperor.

His friend and closest collaborator, Giacomo della Chiesa, who soon succeeded Pius X as Pope Benedict XV, presided over his funeral ceremonies.

On 19 June 1929, twelve days after the Italian Parliament ratified the Lateran Treaty, the body of Cardinal Rampolla was transferred to Santa Cecilia in Trastevere.