Recent exploration has identified a series of Cu-Mo skarn deposits within the Xuancheng-Magushan orefield. The orefield forms part of the Nanling-Xuancheng mining district, which is located within the Middle-Lower Yangtze River Metallogenic Belt (MLYRMB) of central-eastern China. However, this area contains thick and widespread unprospective sedimentary cover sequences that have impeded traditional approaches to mineral exploration. This study presents the results of 3D numerical simulation modeling that identifies possible mineral exploration targets within the entire Xuancheng-Magushan orefield. This modeling enables the identification of unexplored areas with significant exploration potential that are covered by thick sedimentary sequences that cannot be easily explored using traditional exploration approaches. This study outlines the practical value of 3D numerical simulation-based targeting in areas with thick sedimentary cover sequences and uses the Flac(3D) software package to couple processes involved in ore formation such as stress, pressure, and heat transfer. Here, we use volumetric strain increments calculated during numerical modeling as the thermodynamic representation of the generation of space during prograde skarn formation, with this space filed by sulfides either penecontemporaneously or soon after magmatism. This process occurred during retrograde hydrothermal ore formation and the genesis of the skarn-type mineralization in this area. The results of the volumetric strain increment calculated during this numerical modeling study matches the distribution of known mineralization as well as delineating eight potential targets that have not yet been explored but represent areas of significant exploration potential within the Xuancheng-Magushan orefield, indicating these targets should be considered prospective for future mineral exploration. One of these targets was also identified during our previous Comsol-based numerical modeling of the formation of the Magushan Cu-Mo skarn deposit. The fact that this area has been identified as prospective using two different numerical modeling methods indicates that this area should be prioritized for future exploration and also validates the numerical modeling approaches used here and in our previous research that more specifically focused on the Magushan skarn deposit. Overall, our study indicates that prospectivity modeling using 3D numerical simulation-based approaches can be both effective and economical and should be considered an additional tool for future mineral exploration to reduce exploration risks when targeting mineralization in areas with thick and unprospective sedimentary cover sequences.