Following on the ambitions of his predecessor Ivan, Vasili conquered Pskov, Ryazan and Smolensk as well as strengthening Russian influence in Kazan and to the Volga region.

[citation needed] Vasili also took advantage of the difficult position of Sigismund of Poland to capture Smolensk, the great eastern fortress of Lithuania (siege started 1512, ended in 1514), chiefly through the aid of the rebel Lithuanian, Prince Mikhail Glinski, who provided him with artillery and engineers.

The loss of Smolensk was an important injury inflicted by Russia on Lithuania in the course of the Russo-Lithuanian Wars and only the exigencies of Sigismund compelled him to acquiesce in its surrender (1522).

Although in 1519 his armies were defeated along the Oka River and 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.

When this proved unsuccessful, Vasili consulted the boyars, announcing that he did not trust his two brothers to handle Russia's affairs and forbade them to marry anyone.

A divorce due to wife sterility was unlawful, so he falsely accused her of witchcraft, and despite much opposition from the clergy, he divorced his barren wife, exiled her to a monastery, exiled the opposed clergy and soon married Princess Elena Glinskaya, the daughter of a Serbian princess and niece of his friend Michael Glinski.