The monastery is most famous for its exceptional fresco paintings, which convey dramatic facial expression and emotions not commonly found in Byzantine art. In 1555 the main dome collapsed, but within a short time the monastery was renewed and repainted. Fragments of old frescoes were incorporated into the new ones. An example of a combination of a new and old painting is the fresco portrayal of The Communion of the Apostles. Among other well-known fresco themes are the Transfiguration, the Raising of Lazarus, the Birth of the Mother of God, the Presentation of the Mother of God to the Temple, The Entry into Jerusalem, and The Descent from the Cross.

The most impressive fresco in St Panteleimon, created under the influence of apocryphal religious literature, is The Lamentation of Christ. Art historians consider it a masterpiece, as it displays traits associated with renaissance art at a much earlier date than the blossoming of the Italian Renaissance.