The monastery was founded by St. Athanasius of Meteora, when he and his spiritual father, Gregory, retreated to Meteora in around 1340 AD. The two monks settled at Megalo Meteoro, in a hermitage located to the left of the staircase leading to the monastery entrance. Brother Athanasius’ renown attracted an ever increasing number of monks, leading to the establishment of the first coenobium at Meteora, along the lines of Athonite monasticism.

The second founder was Joasaph, a disciple and successor of Athanasius.  He was the son of Symeon Uroš Palaeologus, despot of Epirus and descendant of the Serbian Nemanjić dynasty, who settled at Megalo Meteoro in 1373. Joasaph collected sizeable donations and fostered a marked increase in building activity, thus lending the monastery considerable prestige.

The monastery became independent and stavropegic in the 16th century under Jeremiah I, Patriarch of Constantinople. From that time on it flourished, especially under brother Simeon, who was the founder of the new catholicon , the refectory and other smaller buildings in the Megalo Meteoro complex.

Over the course of its 600 year history the monastery has been attacked and looted many times: by the Saracens in 1609 and by Arslan Pasha in 1616, while it was extensively damaged by fire in 1633.

The monastery catholicon, the Church of the Transfiguration, is perhaps the most impressive of the Meteroa catholica, and was built in three construction phases. The Church of St. Athanasius belongs to the first phase, and is a typical cross-in-square church , parts of which were incorporated into the masonry of the newer Bema . The triconch cross-in-square church erected by Athanasius’ successor Joasaph dates to the second phase, when rebuilding and expansion work was carried out in 1388. The new catholicon was built during the third construction phase, in 1545. Its cloisonne masonry is finely crafted and, though not bombastic, commands attention.

The wall paintings adorning the interior of the church were likewise completed in three phases. The scene of the Second Coming still visible on the exterior of the north wall belongs to the first phase, shortly after 1388. The paintings from the old catholicon - those on the present day Bema - date to 1483, with the exception of those in the dome and the apse , which come from the third decoration phase, in 1552. The dynamic, detailed, richly coloured decoration in the older catholicon, completed over a period of thirty years, remains true to Byzantine iconography and the composite designs of Palaeologan art, while also being enhanced by secondary iconographic details from western art, notably Italian Late Gothic painting. The entire composition of the old catholicon is attributed to a workshop from Kastoria which was active in the region of Thessaly, Western and Central Macedonia and the wider Balkan Peninsula (Serbia, Bulgaria, Moldova). The sumptuous iconography in the new church is influenced by Athonite models and Palaeologan traditions, with a modicum of fully assimilated loans from Western art. The style and artistic choices made by the anonymous artists attest their close relation to the Cretan School and Theophanes of Crete, who painted the Church of St. Nicholas Anapafsas in 1527, while still a young man. Furthermore, the new catholicon of the Transfiguration was quite possibly the work of the Cretan painter Tzortzis, a pupil of Theophanes, together with members of his workshop.

One remarkable feature of the interior is the carved wooden templon , lavishly decorated in a multitude of themes. The oldest surviving part of this lies over the sanctuary door; it dates back to 1634/5 and is signed “by the hand of Master John”.  However, most of the templon was replaced in 1791, being the work of a certain Constantine from Linotopi and Kostas from Metsovo.

Abbuting the south side of the sanctuary is the Chapel of St John the Baptist, a small domed building dating to the 18th century.

To the southwest of the catholicon lies the chapel of Saints Contantine and Helen, built in 1789 under Abbot Parthenios and financed by Dionysius the monk and his son priest-monk Zachariah.

The monastery refectory, founded by Αbbot Simeon, was built to the north of the church and inaugurated on August 10th 1557. It is a vaulted oblong building ending in a polygonal apse to the east, and divided internally into two aisles by a five columned colonnade . The building presently functions as a museum.

The monastery kitchen was built adjacent to the north side of the refectory. A spacious square room covered by a hemispherical vault and crowned by a small dome, it likewise serves as a museum open to visitors.

The monastery also had a hospital, located opposite the sanctuary of the catholicon. It was founded at  the same time as the nursing home, in 1572. In a previous phase this imposing domed structure stood two storeys high.