The square chancel of the 12thc. cathedral is enclosed between the early 14thc. choir and 19thc. nave of the present Church of Ireland Cathedral.

A monastery was founded in Tuam by St Jarlath during the 6thc. In the 12thc. Tuam became particularly important as one of the principal residences of the O'Connor kings of Connaght. During the reign of Turlough O'Connor (1106–1156) the dynasty met with particular military and political success leading up Turlough's claim to the title of Ard Rí of Ireland. Turlough was also a patron of the arts, commissioning the Cross of Cong between 1119 and 1136 which was designed to enshrine a fragment of the True Cross which Turlough himself had obtained. At Tuam, with the abbot, he enlarged the monastic enclosure in 1127, and 13 years later founded an Augustinian priory there. He was also involved in the erection of two high crosses. On account of its royal connections Tuam was actively involved with the 12thc. church reform, and Turlough's patronage of the monastery was probably a calculated effort to acquire a metropolitan see. In 1152 Aedan O'Oissin, comarb or abbot of Tuam became the first archbishop.

Turlough was succeeded by his son Rory (1158–98). Rory became Ard Rí in 1166 and despite the Anglo Norman invasion and a Norman raid on Tuam in 1177, maintained authority in his own kingdom at least until 1183, when family feuding weakened his position. In 1184 there is a record in the Annals of Lough Cé that the ‘great church of Tuaim-da-ghualann fell in one day, both roof and stone’, suggesting that the current chancel probably belongs to the replacement structure. The early chancel has survived being incorporated into two later buildings. There are few descriptions of the chancel prior to the 19thc. The construction of the gothic choir can be dated to 1312 when the Dean was granted 'relaxation of a hundred days of enjoined penance to those who contribute to the rebuilding of Tuam Cathedral, begun by the late Archbishop William [de Birmingham, 1289–1312] and continued by the Dean Philip, who petitions for aid to complete it'. The choir was built eastwards of the early chancel and a 'chapter room' was constructed off the N wall. In 1555 it was stated that the cathedral at Tuam was 'properly furnished', but its belfry was in ruins. In 1561 David Wolfe, the Papal Legate in Ireland stated that the cathedral had been used as a fortress for the local gentry for over three hundred years and that they stabled their horses in it . The cathedral was redecorated shortly after John de Burgo became Catholic Archbishop in 1647. In 1688 Archbishop Vesey rebuilt the tower, an event recorded by a plaque on the new build, other minor repair works may also have been carried out at this time. The earliest surviving written description of the cathedral in c. 1672 by John Lynch describes the building as falling down. It appears that the original nave, belonging to the early church survived until the mid 18thc. when it was destroyed by fire. In the early 19thc. the chancel was converted into a porch for the gothic choir. The span of the arch was filled with a wooden door and an inner doorway was cut through the central light of the E window. Writing in 1845, Petrie noted that the cathedral was in a ruinous state. In 1863 the construction of a new cathedral around the existing fabric was commenced by Thomas N. Deane.

The Romanesque sculpture at Tuam cathedral is amongst the highest quality and best-preserved in the country. The chevron motifs on the chancel arch find their closest parallels at Killaloe where the cogwheel chevron is particularly close in form, and the otherwise unusual cross bands on the apices of the chevron is also found.

The E window is also unusual. It is amongst the earliest examples of a triple-light window in the country. Earlier examples may have existed in a Cistercian context at Jerpoint and Boyle, but are unlikely to have had anything like the elaborate decoration found on the Tuam windows.