Groundwater resources play the single most important role in the delivery of potable water to rural communities in northern Ghana, especially during the long dry season and where surface water sources are polluted or non-existent. This study sought to assess the quality and main controls on groundwater chemistry in parts of Sawla-Tuna-Kalba District in the Savannah Region of Ghana. Multivariate statistical analysis and conventional hydrochemical plots were employed in the analysis of 112 groundwater samples from the study area. Conventional graphical methods, R-mode Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA) identified dissolution of silicates and the influence of agrochemicals and domestic wastewaters as the main sources of variations in the hydrochemistry in the study area. Q-mode HCA coupled with Stiff diagrams identified Ca–HCO3 water type in recharge areas, and Mg–Ca–HCO3 water type, which evolves into a Ca–Na–K–HCO3 water type in discharge areas in the groundwater flow regime. Mineral stability diagrams indicate the groundwater is stable in kaolinite, which suggests little or no restricted groundwater flow conditions. Groundwater quality for domestic purposes was assessed using the weighted arithmetic index approach. The computed water quality indices (WQIs) from the data suggest that 94% of the sampled boreholes provide groundwater of “excellent” quality for drinking purposes, whereas 5% and 1% present water of “good” and “poor” quality respectively. Spatial interpolation of the estimated WQIs suggests the quality of the groundwater in the study area is suitable for domestic purposes. The assessment of the groundwater quality for irrigation purposes suggests the water is of “excellent” to “permissible” quality and may be used for irrigation without prior treatment.