A human health risk assessment of artisanal miners exposed to toxic metals in water bodies and sediments in the PresteaHuni Valley District of Ghana was carried out in this study, in line with US EPA risk assessment guidelines. A total of 70 water and 30 sediment samples were collected from surface water bodies in areas impacted by the operations of artisanal small-scale gold mines in the study area and analyzed for physico-chemical parameters such as pH, TDS, conductivity, turbidity as well as metals and metalloids such as As, Cd, Hg and Pb at CSIR—Water Research Institute using standard methods for the examination of wastewater as outlined by American Water Works Association (AWWA). The mean concentrations of As, Cd, Hg and Pb in water samples ranged from 15 μg/L to 325 μg/L (As), 0.17 μg/L to 340 μg/L (Cd), 0.17 μg/L to 122 μg/L (Pb) and 132 μg/L to 866 μg/L (Hg), respectively. These measured concentrations of arsenic (As), mercury (Hg), cadmium (Cd) and lead (Pb) were used as input parameters to calculate the cancer and non-cancer health risks from exposure to these metals in surface water bodies and sediments based on an occupational exposure scenario using central tendency exposure (CTE) and reasonable maximum exposure (RME) parameters. The results of the non-cancer human health risk assessment for small-scale miners working around river Anikoko expressed in terms of hazard quotients based on CTE parameters are as follows: 0.04 (Cd), 1.45 (Pb), 4.60 (Hg) and 1.98 (As); while cancer health risk faced by ASGM miners in Dumase exposed to As in River Mansi via oral ingestion of water is 3.1 × 10−3. The hazard quotient results obtained from this study in most cases were above the HQ guidance value of 1.0, furthermore the cancer health risk results were found to be higher than the USEPA guidance value of 1 × 10−4 to 1 × 10−6. These findings call for case-control epidemiological studies to establish the relationship between exposure to the aforementioned toxic chemicals and diseases associated with them as identified in other studies conducted in different countries as basis for developing policy interventions to address the issue of ASGM mine workers safety in Ghana.