The seismic response of a medieval church in Central Italy is analyzed considering the two roof configurations, i.e., reinforced concrete and timber roofs, that the church had in different periods of its existence. Structural interventions and changes are common in the churches of this territory, where frequent earthquakes put these buildings at risk. The church studied here, St. Salvatore in Acquapagana (Serravalle di Chienti, province of Macerata), was damaged by the 1997 Umbria-Marche and the 2016 Central Italy earthquakes. Between these two seismic events, the church was repaired, and the concrete roof was substituted with a lighter timber roof. To investigate the influence of this change on the seismic response, a study was performed at the building and façade macroelement scales using the finite element model and rigid body spring model, respectively. For each approach, the two roof configurations were considered, and two strong motion records, from September 26, 1997, and October 30, 2016, were applied. The results show that the concrete roof improves the box-like behavior, but it increases the vulnerability of the masonry structures, characterized by a limited tensile strength. Conversely, in the timber roof configuration, the most vulnerable areas of the structure are the intersections between structural elements.