The current article presents a case study of the settlement response of the historic Hoca Pasha Mosque that involves uncertainties arising from the complex excavation activities, soil properties, building materials, and geometry and the presence of pre-existing cracks in the mosque's walls. The objective is to demonstrate the added value of a two-stage numerical analysis approach for the assessment of the settlement response of the building. The first stage comprises analyses of the structural behavior using the monitored settlements for each wall. The second stage examines the behavior of the complete building as a whole. The effects of soil-structure interaction and the pre-existing cracks are considered through discrete interface elements. It is shown that executed simulations can reasonably reproduce the overall settlement response, resulting stresses and the pre-existing crack activities. The parametric analyses in the second stage also produce generalizable results, of use beyond the specific case. Namely, as the soil/structure stiffness ratio increases the settlement-induced vulnerability increases. Including soil-structure interaction in the analyses reduces tensile strains due to differential settlements. Including pre-existing cracks reduces tensile strains in the vicinity of the cracks but results in an increase of stresses in neighboring sections.