The health of the lower basin of the Volta River in Ghana was evaluated in January–February and May–June 2016 using physicochemical parameters and benthic macroinvertebrates sampled at 10 locations. Selected environmental variables were compared to accepted environmental water quality standard values where applicable. Principal component analysis (PCA) and redundancy analysis (RDA) were used to analyse the association between the benthic macroinvertebrates distribution and physicochemical variables. Pesticide concentrations were generally below the limit of detection 0.01 and 0.005 µg/L for organophosphate/synthetic pyrethroid and organochlorines respectively. Nutrient levels were also generally low; however, significant differences existed between the values of physicochemical parameters at the different sampling sites and seasons (Monte Carlo permutation test; p = 0.002), as well as between the abundance of macroinvertebrates at the different sites and seasons (p = 0.002). The environmental variables dissolved oxygen (DO), phosphate, pH, substratum (p < 0.05), turbidity, conductivity, total dissolved solids, total solids and nitrate (0.05 < p < 0.10) significantly explained the variation in macroinvertebrate composition between sampling stations in the Volta River. Polypedilum fuscipenne, was positively correlated with turbidity and DO concentrations; Physa sp., Centroptilum sp., Centroptiloides sp., Phaon iridipennis and juvenile fish were positively correlated with nitrate concentration and pH and negatively correlated with turbidity and DO. Polluted sites were dominated by the snail Lymnaea glabra. This demonstrates that physicochemical parameters and macroinvertebrates could be applied to describe the water quality and improve the biomonitoring for water resources management and the environmental protection in the Lower Volta River.