Drawing on the DFID’s sustainable livelihood framework, this paper explores the nexus between artisanal and small-scale mining (ASM) and livelihood in Prestea mining region, Ghana. A cross-sectional mixed method survey involving simple random and purposively sampled participants () was carried out. The results suggest both positive and negative relationships between ASM and livelihoods of the people. The study found various livelihood assets associated with ASM and how critical assets are adversely affected by ASM activities. Limited employment opportunities in rural areas (82%), economic hardships/poverty situations of people (59%), and “quick” income earnings from ASM (90%) were the major factors that influenced people to combine and use their personal assets to enable them to engage in ASM. ASM contributes to the livelihood enhancement through income generation, increased well-being and asset acquisition (50.7%), reduced vulnerabilities (31.1%), and empowerment of people (19.2%) to establish other economic activities. However, the small-scale miners and farmers as well as farmlands, forest, and water resources are most vulnerable to adverse effects of ASM activities. Accidents of various degrees, diseases, and death were the shocks in ASM. Regarding the massive impact of ASM on employment creation and poverty reduction in rural communities, it is recommended that stakeholders recast Ghana’s mineral policy to ensure concurrent environmental sustainability and socioeconomic development.