The design of the cathedral draws from architectural designs found in Jerusalem, and holds strong religious meanings. When seen from the top, the eight domes surrounding the ninth dome in a circular fashion appear to form a star.
Because the church has no analog—in the preceding, contemporary, or later architecture of Muscovy and Byzantine cultural tradition, in general—the sources that inspired Barma and Postnik are disputed.
Ascension Church in Kolomenskoye has become an improbable influence on the St.Basil Cathedral. Another enormous influence had the influence of Italian architects. There was a large group of Italian architects and craftsmen continuously worked in Moscow in 1474–1539, as well as Greek refugees who arrived in the city after the fall of Constantinople. These two groups, helped Moscow rulers in forging the doctrine of Third Rome, which in turn promoted assimilation of contemporary Greek and Italian culture. Many historians noted the resemblance of the cathedral's floorplan to Italian concepts by Antonio da Sangallo the Younger and Donato Bramante, but most likely Filarete's Trattato di architettura. Other Russian researchers noted a resemblance to sketches by Leonardo da Vinci, although he could not have been known in Ivan's Moscow. The interior of the St Basil's Cathedral greatly differs compared to its exterior, comprising of modest decorations and narrow corridors.