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 NO as a proxy, this study mainly focused on the status of GW contamination, origins of NO and potential human health risks through integrated hydrochemistry, correlation analysis, isotopes (N, δO), 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. NO in GW ranged from 0.12 to 733 mg/L with average 59.6 mg/L and positively correlated with K, Ca, Mg Cl, Na and EC. In SW, a maximum of 5.3 mg/L of NO was observed. Largely, 75% of the GW exceeded local background NO 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 NO, Cl, SO and K to GW in the basin. From NO/Cl ratio, 43% of the GW and 21% of SW were affected by effluents and agrochemicals. Values for δN-NO and δO-NO 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 NO contamination of water in the basin. The Bayesian model apportioned 80% of GW NO 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 NO contamination to infants. Immediate measures for GW and SW quality protection are recommended.