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Masonry structures are complex systems that require detailed knowledge and information regarding their response under seismic excitations. Appropriate modelling of a masonry structure is a prerequisite for a reliable earthquake-resistant design and/or assessment. However, modelling a real structure with a robust quantitative (mathematical) representation is a very difficult, complex and computationally-demanding task. The paper herein presents a new stochastic computational framework for earthquake-resistant design of masonry structural systems. The proposed framework is based on the probabilistic behavior of crucial parameters, such as material strength and seismic characteristics, and utilizes fragility analysis based on different failure criteria for the masonry material. The application of the proposed methodology is illustrated in the case of a historical and monumental masonry structure, namely the assessment of the seismic vulnerability of the Kaisariani Monastery, a byzantine church that was built in Athens, Greece, at the end of the 11th to the beginning of the 12th century. Useful conclusions are drawn regarding the effectiveness of the intervention techniques used for the reduction of the vulnerability of the case-study structure, by means of comparison of the results obtained.