This paper presents the seismic vulnerability assessment of a monumental masonry building located in Southern Italy, focusing on the modelling challenges associated with such a complex structure. The case study was constructed between 1750 and 1756 during the reign of Charles of Bourbon. The entire complex has a rectangular plan (157 m × 125 m) with an internal courtyard (108 m × 77 m). The structure consists of three above-ground floors. At each of the four corners, the building is defined by tower-like volumes known as bastions (25 m × 25 m), which contain not only rooms but also stairwells that provide access to the upper levels—supplementing those located in the front and rear wings. For the purpose of this vulnerability assessment, the building was divided into eight portions. Six structural models were analysed individually, assuming them to be isolated from the adjacent sections. In addition, to account for the good structural continuity of the building, a global AS-IS model was also developed and analysed. The results of the nonlinear analyses are presented: pushover analyses were carried out using the equivalent frame modelling approach for both the local (isolated) and global (AS-IS) models. The comparison of results allows for key observations to be drawn and helps identify more suitable modelling strategies for the seismic analysis of complex masonry buildings.