In order to correctly define the pathology of multiple-leaf stonemasonry walls and determine the appropriate interventions for its conservation and preservation, comprehensive studies on its building materials should be carried out since the overall behaviour of masonry structures is highly dependent on the characterization of its construction materials. Consequently, an interdisciplinary procedure for construction material characterization used in multiple-leaf stone-masonry walls in Egypt has been implemented to enrich documentation, conservation and restoration issues of this type of wall. The research methodology integrates experimental data obtained through on-site sampling, conducted tests and analyses, historical information, and field survey observations. The fundamental physical and mechanical properties of the masonry elements were examined by incorporating stone blocks, mortars and core-infill materials. The mineralogical composition and interlocking textures of the collected samples were investigated utilizing a large range of complementary investigation and analysis techniques, including polarizing microscopy, X-ray diffraction (XRD), thermal analysis (TG/DTA), and environmental scanning electron microscope (ESEM) attached to an EDX unit. Through the results thus obtained, a complete characterization of the mineralogical composition; physical–mechanical, chemical, and thermal properties; and the interlocking textures of the construction materials of both the outer and inner-core layers was performed. The outer leaves of the majority of the multiple-leaf stone-masonry walls in medieval architectural heritage were mainly built of well-dressed limestone blocks with nearly uniform dimensions, while the inner-core layer was usually built of stone-rubble infill with bending lime-based mortar. The uniaxial compressive strengths of core infill (corresponding to the inner core layer) and lime-based mortar of the embedded joints are shown to be 85 and 92.5% lower than the limestone units of the outer layer, respectively. Moreover, experimental observations indicate that the inner core layer exhibits the highest porosity values; consequently, deteriorated, loose and cohesionless core infill could greatly affect the durability and thermal resistivity of this kind of wall. The results provide scientific support for investigating the overall structural behaviour of this type of walls and for decision-making in future conservation and restoration strategies.