Many children under five years still die from diarrhoeal diseases globally even though much progress has been made. The threat to public health posed by diarrhoeal diseases warrants the need to understand the interaction of the disease determinants from a spatio-temporal perspective to inform policy and intervention design. In this study, a pooled regression analysis was carried out using the Ghana Demographic and Health Survey data on 15,808 children under five years, to assess the combined effect of environmental factors on childhood diarrhoea prevalence and morbidity over a twenty-one-year period. Childhood diarrhoea prevalence declined steadily from 20% to 16% from 1993 to 2003 but increased to 20% in 2008 and finally decreased significantly to 12% in 2014. The strength of the association between diarrhoea prevalence and each of the predictors presented in decreasing order of magnitude were as follows: current age of child, geographical region, religion, mother's highest educational level, ethnicity, source of drinking water and toilet facility, residential wellbeing, birth order, age of mother, and sex of child. Regional and temporal heterogeneities in prevalence, rate and distribution of diarrhoea were observed indicating the need for context-specific interventions and policies.