The Church of Hagios Nikolaos Orphanos (Ναός του Αγίου Νικολάου του Ορφανού) can be found in the Upper Town, near the western walls of Thessaloniki. It is one of the 15 Paleochristian and Byzantine Monuments of Thessaloniki that were included in the UNESCO World Heritage List in 1988.
The church was built as the katholikon of a monastery in the second decade of the 14th century. It was probably founded by the Serbian ruler Milutin. All that survives of the monastery complex are, in addition to the katholikon, a few remains of the entrance to the propylon, with two columns, in Irodotou Street, indicating that the present road follows the same line as the old Byzantine street. 
During the period of Turkish domination, the church was a metochion of the Vlatadon Monastery. The church no longer has its original form, which will have been that of a three-aisled basilica. Its core consists of a long, timber-roofed hall enclosed on three sides by an ambulatory. This is covered by lean-to roofs, at a lower level than the one over the main area, and terminates at the east in two symmetrically placed chapels. The nave communicates with the north and south arms of the ambulatory through double-arched openings and with the west, which acted as a narthex, by a small entrance. The masonry is plain, and lacks the variety of the decorative brickwork so characteristic of the Palaiologan churches in the city. 
The sculptural decoration is confined to the reused Early Christian capitals, which have two rows of sawn acanthus leaves, and the marble iconostasis contemporary with the church, which is to be found in situ, almost intact.
The wall paintings form one of the most completely preserved ensembles in the churches of Thessaloniki and, through the clarity of their iconographical program, give expression to the classical conception of Palaiologan mural art. The sacred story is narrated in a series of zones, following the prevailing sequence used in the painted decoration of Byzantine churches, which symbolizes and reflects the hierarchy of the heavenly Church.
In the nave, at the lowest level, military and healing saints are depicted, full length and in bust. The representations of the Virgin Paraklisi and Christ the Savior, near the sanctuary, and the figures of Saint John the Baptist and Saint John the Theologian that accompany them, are of particular importance for their eschatological meaning. The higher levels of the north, south and west walls narrate the Passion, interposed with which, over the west entrance, is the scene of the Dormition of the Virgin, from the cycle of the Dodekaorton. The Twelve great festivals of Christianity and scenes narrating the events after the Resurrection occupy the higher parts of the walls of the nave and the sanctuary. In this area, where the Mystery of the Divine Eucharist was celebrated, the subjects depicted have a symbolic character: on the apse is the Virgin in an attitude of supplication between two archangels, and below her, the Melismos and Concelebrating Hierarchs. Hierarchs and Church Fathers are also painted on the vertical walls of the sanctuary; above them, on the east wall, is a scene of the Communion of the Apostles and the Ayion Mandelion. The south wall of the north arm of the ambulatory has depictions, at the bottom, of full-length saints, above which are two zones containing scenes from the Akathistos Hymnos. On the north wall of the south arm of the ambulatory the bottom register has episodes from the Life of Saint Gerasimos of Jordan and the Burning Bush from the cycle of biblical prefigurations of the Virgin. In the narthex, finally, in addition to the zone of saints, there is an extensive cycle from the Life of Saint Nicholas and scenes from the Menologia. The wall-paintings in the Church of Hagios Nikolaos date from the decade 1310-20, and are one of the most important painted ensembles of the early 14th century, not only in Thessaloniki but in the wider area of Macedonia and Serbia. Amongst the virtues of the anonymous painter should be counted the clarity of his narrative of the sacred story, which is confined to the essential and made comprehensible to the faithful, his adherence to a measured sense of proportion, his feeling for color, and his maturity in the handling of the medium.