The monastery was probably built in the mid-14th century by Manuel Kantakouzenos, the first Despot of the Morea — the Byzantine ruler who governed the Peloponnese as a semi-autonomous principality. The construction is unusual: the building is embedded into the cliff face, with a natural cave forming part of its structural foundation. This integration of natural rock into ecclesiastical architecture is characteristic of the 'Mystras style,' a local building tradition that the Peribleptos exemplifies: churches that resemble small fortresses, constructed of squared stones with inlaid tiles, their profiles shaped by the terrain rather than imposed upon it. The complexity of the exterior — irregular surfaces, projecting apses, varied roof levels — creates, inside, the kind of dramatic spatial variety that fresco painters dream of.

The frescoes covering the interior of the Peribleptos church were painted between approximately 1348 and 1380. They constitute a very rare surviving late Byzantine fresco cycle — not individual panels or fragments but a comprehensive program of New Testament images, flowing from surface to surface with what scholars have described as a 'perpetual flow,' one scene leading organically into the next. The curved surfaces of the apse and the undulating walls of the cave-supported structure gave the painters an unusual canvas, and they used it: the images wrap and turn, drawing the viewer's eye around the interior in a continuous narrative. The style has been connected to both the Cretan and Macedonian art schools, though the painters themselves are not identified. The frescoes have been described as 'delicate and subdued' — a restraint that serves them, giving the figures a luminous, contemplative quality.

Among the specific images preserved here is a fresco of Saint John the Baptist in the scene of the Baptism of Christ, one of the great set-pieces of Byzantine iconographic tradition. The monastery also holds an extraordinary relic: the head of Saint Gregory of Nazianzus, the 4th-century Archbishop of Constantinople and one of the three Cappadocian Fathers, whose theological writings shaped the Orthodox understanding of the Trinity. His presence here — both as a painted figure in the iconographic program and as a physical relic — underscores the Peribleptos's status as a place of genuine spiritual and ecclesiastical importance, not merely aesthetic distinction. The Virgin Mary as the dominant devotional focus of Mystras's churches and monasteries is evident here too, in the Marian imagery woven throughout the fresco program.

Mystras fell to Ottoman forces in 1460, and the Peribleptos, like most of the city's churches, changed hands and function during the centuries of Ottoman and Venetian rule. Byzantine art and architecture survived the conquest in a more than nominal sense: as scholar Karin M. Skawran observed, painting in the region retained its monastic, Constantinople-derived character even as political control changed. The extensive fresco cycle at Peribleptos was not destroyed. It endured. Whether this was because the building's tucked-away position afforded it some protection, or because of decisions made by whoever controlled it during various periods, the result is that a visitor today can stand in a 14th-century Byzantine church and see essentially what a 14th-century Byzantine worshipper saw: the walls alive with figures, the cave behind them, the sacred made tangible in paint on stone.