According to medieval Georgian annals, the construction of the original church on this site was initiated by King Vakhtang Gorgasali in the 5th century.

A hundred years later, Guaram, the prince of Iberia (Kartli), in c. 575 began building a new structure, which was completed by his successor Adarnase in circa 639.

The cathedral's interior took on a different look between 1850 and 1860, when the Russian artist and general Knyaz Grigory Gagarin (1810–1893) composed an interesting series of the murals, though a number of medieval frescoes were lost[clarification needed] in the process.

To the left of the altar is the venerated Grapevine cross which, according to tradition, was forged by Saint Nino, a Cappadocian woman who preached Christianity in the Caucasus in the early 4th century.

The Sioni Cathedral is a typical example of medieval Georgian church architecture of an inscribed cross-in-square design with projecting polygonal apses in the east façade.

The dome with the tholobate is supported by the altar wall and two freely standing pillars (a more advanced design that appeared after the 11th century).

The façades are simple, with few decorations, although there are bas-relief carvings of a cross and a chained lion on the western side and an angel and saints on the north.

[4] Complete in 1812, the bell tower was commissioned under Pavel Tsitsianov using money awarded in recognition of his conquest of Ganja for the Russian Empire.

The Sioni Cathedral serves as a burial ground for several notable churchmen, including the 20th-century Catholicoi-Patriarchs of Georgia, and economic and political figure Giorgi Maisashvili: