Mineral prospectivity mapping (MPM) is a multi-criteria decision-making process that identifies and prioritises potential zones for mineral exploration. Multi-index overlay and fuzzy logic models were employed in this paper to conduct GIS-based MPM of the Ahafo gold district, which is located on the northwestern margin of the Sefwi granitegreenstone belt in Ghana. Mineralisation in the area is structurally controlled with a high degree of hydrothermal alteration. Therefore, the mineral systems approach was used to translate the understanding of orogenic gold hydrothermal system into mappable exploration criteria, leading to the generation of nine evidential layers. These layers represented mappable spatial proxies for active fluid pathways (i.e. proximity to NEstriking basement faults: D2 to D3), physical traps (i.e. proximity to N- to NNE-strike sinistral fault: D4; proximity to litho-contacts; proximity to the intersection of N- to NNE- and NE-strike faults; density of N- to NNE- and NE-strike faults; litho-competency contrast), and chemical traps (i.e. proximity to Fe-rich dykes; litho-reactivity contrast; proximity to hydrothermal alteration zone), all of which are critical for hydrothermal fluid migration, focusing, and gold deposition. Weights and confidence factors were assigned to the evidential layers in the fuzzy logic approach based on experts' knowledge of how the layers are relevant to orogenic gold mineralising processes. In contrast, weights were assigned to layers in the multi-index overlay model based on prediction-area (P-A) plots and normalised densities, limiting the subjectivity of assigning weights to the layers. In order to delineate potential zones for lode-gold mineralisation in the study area, the weighted evidential layers were combined to create multi-index overlay and fuzzy prospectivity maps. The continuous prospective scores of the prospectivity maps were discretised and classified using a concentration-area (C-A) fractal model. The resulting discretised prospectivity maps based on the location of 18 known lode-gold occurrences (i.e. deposits and economic prospects) were further evaluated using P-A plots. The discretised multi-index overlay prospectivity map predicted 76% of known lode-gold occurrences, with 24% of the study area as prospective, whereas the discretised fuzzy prospectivity map predicted 74% of known lode-gold occurrences, with 26% of the study area as prospective. The high potential zones identified on the prospectivity maps were spatially located in areas with structural complexity along: (i) NE-SW structural trends (i.e. 40°–50°); and (ii) secondary structural trends in the NS to NNE-SSW direction (i.e. 0°–10° and 15°–25°). These structural trends control lode-gold mineralisation in the Ahafo gold district..