A significant population within the Lower Volta River Basin of Ghana relies solely on untreated groundwater (GW) and surface water (SW) for various purposes. However, negative practices associated with increasing human activities pose threats to particularly GW quality in the basin. Using NO3− as a proxy, this study mainly focused on the status of GW contamination, origins of NO3− and potential human health risks through integrated hydrochemistry, correlation analysis, isotopes (15N, δ18O), Bayesian and USEPA human health risk models. Slightly acidic to alkaline GW and SW environments were observed. Electrical conductivity (EC) values above 1000 μS/cm were recorded in 45% of the GW with a maximum of 19370 μS/cm. NO3− in GW ranged from 0.12 to 733 mg/L with average 59.6 mg/L and positively correlated with K+, Ca2+, Mg2+, Cl−, Na+ and EC. In SW, a maximum of 5.3 mg/L of NO3− was observed. Largely, 75% of the GW exceeded local background NO3− value of 2.1 mg/L, while 35% were above the WHO recommended value of 50 mg/L. Bivariate and correlation relationships elucidated human contributions to sources of NO3−, Cl−, SO42− and K+ to GW in the basin. From NO3−/Cl− ratio, 43% of the GW and 21% of SW were affected by effluents and agrochemicals. Values for δ15N–NO3- and δ18O–NO3- ranged from +4.2‰ to +27.5‰ and +4.5‰ to +19.9‰ for GW, and from +3.8‰ to +14.0‰ and +10.7‰ to +25.2‰ for SW. Manure, septic effluents and mineralized fertilizers are sources of NO3− contamination of water in the basin. The Bayesian model apportioned 80% of GW NO3− contamination to sewage/manure. Hazard index indicated 70%, 50% and 48% medium to high-risk levels for infants, children and adults respectively, with 79% high-risk of SW NO2− contamination to infants. Immediate measures for GW and SW quality protection are recommended. Display omitted •Linkage established between NO3−, groundwater chemistry and anthropogenic impacts.•Manure, effluent and fertilizers are main sources of NO3− contamination.•The posterior probability distributions of groundwater NO3− varied significantly.•Medium to high human health risks posed by NO3− and NO2− in drinking water.•Outcomes can create awareness for groundwater quality protection and management.