Mesa Gonia is connected to the Panagia Episkopi via a partially paved road, which ends in a parking area directly north of the church.

The red, green, yellow and blue glass bricks provide the only exterior light into the chancel, that is otherwise only lit through the opened doors of the iconostasis, or through it from the inner part of the church.

Due to the addition of annexes, the interior of the Panagia Episkopi has a number of larger and smaller rooms, which gives the church a labyrinthine appearance.

The best known and most valuable icon in the church is that of the Panagia Glykofilousa (Παναγιά Γλυκοφιλούσα – "sweetly kissing Madonna"), dated to the 12th century.

The iconostasis, which separates the eastern end of the main hall of the church from the chancel (called the "bema" in Orthodox tradition), is notable for its brilliantly multicoloured effect.

The upper part consists of an engraved wooden post-Byzantine architrave, a frieze with fourteen icons and a carved top.

[3] The variety of ornaments is considered unique in the Middle Byzantine Era, with links to the 6th century[2] and to churches in Constantinople, Venice and Ravenna.

The door panels display valuable wood carvings from the 17th century with floral motifs and two dragons as an upper finishing for the design.

[5] The northern and southern portals to the chancel, apart from the load-bearing pillars, are covered with man-sized icons of the archangel Gabriel (left) and Saint Menas (right).

The figures in the pictures are reminiscent of Cappadocian murals, which led the Greek construction researcher and Byzantinologist Anastasios Orlandos to conclude that the artist was of eastern origin.

The fresco shows the king on his throne, pointing at his wife, Herodias, as she presents him with the head of John the Baptist on a platter.

Various parts of the building show evidence of the use of spolia from ancient Thera, a city on the Mesa Vouno, a foothill of the Profitis Ilias.

In 1701 a further legend was recorded,[13] relating that the Byzantine Emperor Alexios I Komnenos (1048–1118) presented the Church with a deed to the entire land outside the former villages of Gonia and Pyrgos Kallistis up to the top of the highest mountain of the island.

[12] There is a demonstrable reference to Emperor Alexios in the now largely destroyed inscription Ἀλέξιος ἐν Χῶ τῶ Θῶ αὐτοκράτωρ Ρωμαίων ὁ Κομνινὸς καì πιστὸς βασιλεύς (Alexios in Christ the God [faithful], autokrator of the Romans, the Komnenos and pious basileus) over the inside of the main entrance.

The motifs in the marble intarsia provide some support for this theory, particularly the representation of birds and the frequent use of crosses are typical of illustrated manuscripts from the time of Alexios II.

[16] Therefore, the foundation of the church before the emperor's death in 1118 is not excluded; various local texts that specify exact dates, are from the 19th century and probably have no factual basis.

The recorded history of the church begins in 1207, when the island of Santorini became part of the Duchy of the Archipelago, controlled by the Venetian Republic, following the Fourth Crusade.

When the island along with the rest of the Aegean was captured in 1537 by Hayreddin Barbarossa for the Ottoman Empire, the Orthodox bishop returned and again assumed the Panagia Episkopi as his seat.

[18] The dispute escalated, and both parties took to arms, so that the conflict was brought to the attention of both the Patriarch Neophytos II and Sultan Ahmed I.

The conflict intensified until 1758, when Patriarch Cyril V of Constantinople decreed that all Orthodox Christians who shared a church with Catholics, would be excommunicated.

The Catholics ignored this decree, feeling secure in the protection of the Western ambassadors in Constantinople, and continued to celebrate Mass in the church.

[20] In 1915, a fire in the Panagia Episkopi destroyed the major part of the books, church documents and priestly robes.

[21] The 1956 Amorgos earthquake,[22] which destroyed large parts of the Mesa Gonias, caused severe damage to the church buildings.