The Pammakaristos was either built or renovated to a large extent by Michael Tarchaniotes Glabas, protostrator of Andronicus II Palaeologus (1282-1328). Many historians and archaeologists, however, believe that the original structure was older and some attribute it to Michael VII Ducas (1071-1078). What is certain is that Tarchaniotes was the founder of the elegant parecclesion added to the south side of the church. It has also been suggested that the original building was erected in the 8th century (Mamboury). In earlier times there was a fragmentary inscription in the sanctuary, reading <<Iwannou frontisma>> (<<taken care of by John>>), but no one has been able to discover to whom it refers. George Pachymeres writing on Tarchaniotes remarks that the Pammakaristos was <<his own monastery>>

Historical evidence reveals the importance of this religious centre, which housed the Ecumenical Patriarchate from 1456 to 1587.The Pammakaristos remained in the hands of the Orthodox Greeks even after the Conquest. It is believed that the famous meeting between the Patriarch Gennadius Scholarius and Mehmet 11 the Conqueror and their discussion on questions of religion, took place here.

When, three years after the Fall of Constantinople, the Patriarchate was shifted from the Holy Apostles to the Pammakaristos (1456), the holy relics and other valuable possessions were transferred to the new see. In the thirdpatriarchy of Simeon I of Trebizond (1466, 1471-74, 1481-86), the local Synod denouncing the <<pseudo-union>> of Florence and regulating relations between the Orthodox and Roman Catholic Churches was convened in the Pammakaristos.