The Ruins of St. Paul’s in Macau is integral to its historic monuments, standing as a remarkable testament to the region’s rich and vibrant history, as well as its profound cultural significance. It has been included as part of the historical center of Macau, China, and has been recognized by the UNESCO World Heritage List since 2005. However, Macau’s vulnerability to tropical cyclones has raised significant concerns about the preservation and protection of these invaluable cultural artifacts. To address these challenges, this study employed advanced 3D modeling techniques and computational fluid dynamics (CFD) simulations to perform a comprehensive analysis of the wind pressure characteristics and safety considerations associated with the Ruins of St. Paul’s. In the CFD analysis, wind pressure acting on the surface of the façade of the Ruins of St. Paul is simulated by considering the effect of wind direction and terrain variations. Then, the computational wind pressure is compared with the calculation obtained from the wind design code. It is found that the wind pressure values obtained from the CFD analysis are consistent with the values calculated from the wind design code. Moreover, the CFD analysis provides additional localized wind pressure information around the opening of the façade. The localized wind pressure information offers very useful evidence for identifying those vulnerable regions on the façade with potential wind pressure concentration and hazards that could affect the exterior of the heritage. This study integrates data from previous maintenance records and on-site inspections, enabling a comprehensive evaluation and formulation of practical recommendations for future maintenance strategies.