The uMgeni River is one of the most polluted freshwater ecosystems in KwaZulu-Natal. The study aims to assess the response of Clarias gariepinus to water contamination at the Nagle and Inanda dams using selected biomarkers. Samples were collected and preserved as per the analyses to be carried out. Generally, Nagle Dam showed good quality water compared to Inanda Dam. The Inanda Dam population showed a relatively higher prevalence of alterations in the gills and liver than that from Nagle Dam. The degree of alterations showed some variability within each population, however, there was no significant difference (p>0.05) between the two populations. Organ indices of 20 denoting moderate alterations were observed for both populations. Although the mean AChE activity and VtG induction showed no significant difference between the two populations (p>0.05); the lowest AChE activity and the highest VtG level, were observed in the Inanda Dam populations. Both histopathologic and biochemical biomarkers show signs of severely compromised fish health in the Inanda Dam compared to those from Nagle Dam. It is thus, evident that the tributaries feeding the uMgeni River downstream of Nagle Dam are resulting in the increase of pollution level in the Inanda Dam.