The frescoes in the church are famous examples of Komnenian-era Byzantine art, depicting scenes from the Passion of Christ and various hagiographical illustrations.

The coloring, dramatic composition and purity of expression displayed in the frescoes are outstanding examples of Byzantine medieval monumental painting in the later 12th century.

In his book, Graham-Dixon questions 16th century Vasari's beliefs that Giotto di Bondone finally turned fresco painting away from the primitive influence of Byzantium.

The frescoes contained within St. Panteleimon at Nerezi are not seen as static, they had the capacity to change into something more obviously human and realistic, anticipating the West's emphasis on depicting Christ as a man of flesh and blood by some 150 years.

The lamentation of Christ fresco is described as being a fusion of life and death in a single image as Mary movingly mourns Jesus, cradling him between her legs.