As a youth he was sent by his parents to the Clementine College in Rome, where he made rapid progress in letters and law.

In 1793 he was consecrated titular Archbishop of Thebes, and sent as nuncio to Poland, where he arrived in March, 1794, shortly before the start of the uprising.

Notwithstanding the difficulty of his own position, he used his influence with Tadeusz Kościuszko on behalf of the Catholic Church, and saved the life of Wojciech Skarszewski, Bishop of Chełm, already condemned to death for collaborating with Russians.

Litta also induced the metropolitans of Gniezno, Poznań, and Lwów to renounce their jurisdiction over the dioceses of the Latin Rite in Russian occupied territory, these being transferred to the new metropolis of Mahiloŭ.

During this exile he translated the Iliad, and wrote a series of letters containing a refutation of the four Gallican Articles of 1682, then the subject of much discussion.

Returning to Rome with Pius VII, Litta was made Prefect of Propaganda, which, under his administration, soon recovered its former status.