This paper focuses on the role played by the clay minerals and microorganisms in the deterioration process of Coptic architecture units at the church of Virgin Mary, Wadi El-Natrun region. For this purpose building materials (mainly mortars and plasters) from the studied church were examined using X-ray diffraction (XRD), X-ray fluorescence (XRF) and scanning electron microscope with energy dispersive spectroscopy (SEM-EDS); in order to identify their composition and were investigated petro-graphically to determine the real response of the masonry structure to the deformation imposed at the endogenous factors. Wall gypsum mortars in the church contain halloysite as a dominant clay mineral while plaster is clay free; concerning microorganisms, the fungal flora Aspergillus glaucus represent the most dominant fungi constituting (22.22%), Aspergillus flavus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus occhraceus, and Aspergillus caudidus were also isolated.