Three aspects of the monastery and the church of St. Nicholas at Mesopotam (Albania) are here taken into consideration. First and foremost the structure of the four domes of the naos on a unique central pillar, together with the relationship between the architecture of the churches in the Despotate of Epirus (13th and 14th centuries) and St. Nicholas, is considered. Secondly the cultural relationship between the two coasts of the Adriatic Sea is studied. The strong influence by Italian artists on the sculptures of the Despotate of Epirus and churches such as St. Nicholas between the thirteenth and fourteenth centuries has been inferred by several scholars and will be addressed once again. Finally, the monastic community, historical events and both structural and architectural aspects of Mesopotam are analysed. The analysis deals particularly with the monastery’s surrounding walls, estimating a possible date for their construction.