Globally, diarrhoea is considered as a major threat to human health and remains a leading cause of mortality and morbidity. Several studies have shown that incidence of diarrhoea is influenced by source of drinking water and mediated by some compositional and contextual factors. However, not much is known about how mediating factors interact with source of drinking water to influence incidence of diarrhoea in Ghanaian adults. This study was carried out to investigate how compositional and contextual factors interact with source of drinking water to influence incidence of diarrhoea. A survey was carried out in fourteen regions of Ghana. A multivariate regression model was used to determine how compositional and contextual factors mediate the effect of drinking water source on incidence of diarrhoea. The results showed that source of drinking water and geospatial (regional) disparities are the two main factors that affect incidence of diarrhoea in Ghana. Households that depended on river as a source of drinking water were 64% more likely to have diarrhoea compared to those who drink from pipe-borne water. Upper West Region recorded the highest incidence of diarrhoea (37%) and Volta Region recorded the least incidence of diarrhoea (less than 1%). Escherichia coli bacteria was detected in all water sources. Streptococcus was detected in all the water samples except dam water. Some of the causes of diarrhoea were found to be beyond the control of individuals warranting the need for government intervention and policy to improve the sanitation in the country. Key words: Childhood, morbidity, mortality, spatiotemporal, water quality.