From 1847 to 1856 Youssef studied philosophy and theology in the Pontifical Greek College of Saint Athanasius in Rome, where he was ordained priest on June 11, 1854.

Back in the Middle East, he was chosen by the newly elected patriarch Clement Bahouth as successor for the See of Acre and Galilee.

In 1889, he dispatched Father Ibrahim Beshawate of the Basilian Salvatorian Order in Sidon, Lebanon, to New York to minister to the growing local Syrian community.

According to historian Philip Hitte, Beshawate was the first permanent priest in the United States from the Near East from the Melkite, Maronite, and Antiochian Orthodox Churches.

[10] He anticipated a negative impact of a dogmatic definition of papal infallibility on relations with the Eastern Orthodox Church and became a prominent opponent of the dogma at the Council.

Speaking at the Council on May 19, 1870, Gregory stated: The Eastern Church attributes to the pope the most complete and highest power, however in a manner where the fullness and primacy are in harmony with the rights of the patriarchal sees.

He and two of the seven other Melkite bishops present voted non placet at the general congregation and left Rome prior to the adoption of the dogmatic constitution Pastor aeternus on papal infallibility.

Gregory and the Melkite bishops subscribed to it, but added the qualifying clause used at the Council of Florence: "except the rights and privileges of Eastern patriarchs.

Leo's encyclical Orientalium dignitas in 1894 addressed some of the Eastern Catholic Churches' concerns on latinization and the centralization of power in Rome.