The seismic assessment of monumental buildings requires the consideration of safety and conservation objectives, both for the building and its cultural heritage assets. In order to face these issues, the paper presents the results of a diagnostic analysis carried out on a specific monumental masonry building: the Civic Museum of the small city of Sansepolcro in Tuscany. The building is one of the most important and renowned civic structures, built by a mediaeval Commune to house the town government, this building is also characterized by the presence of one of the masterpieces of late 15th-Century Renaissance art: “the Resurrection”, a large fresco painted by Piero della Francesca. Within this context, three modelling strategies of different complexity are proposed: equivalent frame model, rigid macro-block model and finite element model. In the first part, a full three-dimensional non-linear static analysis and a more simple approach directly based on the limit analysis theorems are used in order to understand the macro-scale structural behavior. Afterwards, the results of the finite element method analyses performed on a detailed 3D model of the wall panel containing the fresco are used in order to investigate the causes of the crack pattern on this important artistic asset.