Vasili III continued the policies of his father Ivan III and spent most of his reign consolidating Ivan's gains. Vasili annexed the last surviving autonomous provinces: Pskov in 1510, appanage of Volokolamsk in 1513, principalities of Ryazan in 1521 and Novgorod-Seversky in 1522. Vasili also took advantage of the difficult position of Sigismund of Poland to capture Smolensk, the great eastern fortress of Lithuania, chiefly through the aid of the rebel Lithuanian, Prince Mikhail Glinski, who provided him with artillery and engineers.

In 1521 Vasili received an emissary of the neighboring Iranian Safavid Empire, sent by Shah Ismail I whose ambitions were to construct an Irano-Russian alliance against the common enemy, the Ottoman Empire.

Vasili was equally successful against the Crimean Khanate. Although in 1519 he was obliged to buy off the Crimean khan, Mehmed I Giray, under the very walls of Moscow, towards the end of his reign he established Russian influence on the Volga. In 1531–32 he placed the pretender Cangali khan on the throne of Khanate of Kazan. Vasili was the first grand-duke of Moscow who adopted the title of tsar and the double-headed eagle of the Byzantine Empire.