Recommended to Catherine by Count P.A. Rumyantsev, with whom he had served in the Russo-Turkish War of 1768–74, Bezborodko was appointed secretary of petitions in 1775. He later became postmaster general and “plenipotentiary of all negotiations” in the Foreign Office, and in 1786 he was promoted to the Senate, wherein he became Catherine's spokesman. In 1792 he concluded the Treaty of Jassy with the Turks, extending Russia's frontier to the Dniester River. He also advised Catherine on the second and third partitions of Poland (1793 and 1795).

After Catherine's death (1796) Bezborodko was made a prince of the Russian Empire and imperial chancellor by Paul I, who, despite their disagreement concerning Russia's attitude toward France, regarded Bezborodko with favour.