Pollution of aquatic resources in Uganda is on the increase and the trends are expected to increase with increase in population size and urbanisation. Assessment and mitigation of the environmental impacts on water quality and biodiversity have now become necessary. The aim of the study was to integrate invertebrate and fish as bioindicators and fish histopathology as a biomarker in the assessment of water quality deterioration in urban wetlands in Uganda. The integration harnesses the advantages and counteracts the shortcomings of each method and thus builds a more robust diagnostic tool that gives a better view of the impacts to the entire ecosystem. Four endpoints which included, physicochemical variables, benthic macroinvertebrate bioindicators, fish bioindicators and fish histopathology biomarkers were compared between varied effluent-impacted wetlands (Murchison Bay in Kampala, and Kirinya, Masese and Winday Bay in Jinja) and a non-impacted reference wetland (Lwanika in Mayuge). Results from the effluent-impacted sites differed from the less impacted reference site. The two sampling locations at Murchison Bay (inshore and offshore) and one sampling location at Kirinya (inshore), that were highly impacted with urban effluent, showed elevated nutrient levels, low pH, dissolved oxygen and secchi depth readings. This corresponded with low invertebrate taxa and fish species diversity and richness; and severe histopathological responses in liver, gonads and gills of O. niloticus. Sensitive taxa such as ephemeroptera and trichoptera were completely absent while pollution tolerant taxa Chironomus sp, Corbicula and Oligochaeta were present. Also notable was the absence of many native haplochromines and presence of mainly Brycinus sadleri, Oreochromis niloticus and leucostictus. The organs manifested high prevalence of severe inflammatory and regressive changes and higher organ indices that fell within the pathological category. These sites were consistently classified as highly polluted under the four endpoints. The reference site was classified as least polluted while Masese and Winday Bay were moderately polluted. Results suggested that the approach of using invertebrate and fish as bioindicators and the fish histopathology as a biomarker, in relation to water quality physicochemical variables was a useful tool in highlighting the spatial differences in environmental quality.