The generation of acid in reactive sulphide-containing rocks is a major global problem confronting advanced countries, and serving as a wake-up call for developing countries like Ghana. South-western Ghana hosts two major gold belts, which house ten large-scale mining companies, several small-scale mining companies, farms and other activities. The presence of sulphur in the rocks, coupled with the land disturbances stemming from the activities mentioned above, suggests the potential for uncontrolled acid generation. These have thus generated interest in studies on mapping out the acid generating potential of these areas, so that proactive steps can be taken to prevent acid mine drainage. In this study, several samples were taken from mine waste, mineralised waste and ore from a mine concession in Ghana, and subjected to mineralogical, geochemical and Acid-Base Accounting (ABA) studies. Mineralogical studies reported about 75% quartz while carbonates, feldspars, pyroxene, sericites and chlorites accounted for 25% of samples tested. Polish sections showed pyrite content of up to 5% while arsenopyrite accounted for 1%. The results from geochemical and Acid-Base Accounting (ABA) passed 31% of the samples as non-sulphidic, whereas 20% had sulphur content above 0.5%. The sulphur content in excess of 0.5% gives an indication that the rock can generate acid. Analysis of paste pH confirmed that about 80% of the samples were neutral to basic (i.e. pH 6.5-8.5). Further analysis using Net Neutralising Potential (NNP) and ratios of Maximum Neutralisation Potential to Acid Production Potential (NP: AP) placed 35% of the samples as having the potential to generate acid since the NNPs were negative, while the NP: AP had values less than 1. This 35% had the capacity to significantly deteriorate natural water quality. The study concludes that there is a great potential for AMD generation in south-western Ghana, and this calls for periodic monitoring and development of proactive neutralising strategies to arrest the situation.