It is unclear how fish in freshwater ecosystems are affected by the combined presence of microplastics (MPs) and anionic surfactant detergents. So, our investigations focus on the nephrotoxic effects of both Polyethylene microplastics (PE-MPs) and Sodium lauryl sulfate (SLS) in single or combined exposure on African Catfish (Clarias gariepinus). In the current study, rearing water of catfish (Clarias gariepinus) was supplied with 0, 10 mg/L PE-MPs, 4 mg/L SLS, or their combination for 15 days. Blood analysis for the kidney functions and histological appraisals for the renal tissue integrity, collagen density (types I & III), and polysaccharide deposits were investigated. Exposure to the irregular-shaped PE-MPs (10 mg/L) or SLS (4 mg/L) revealed nephrotoxicity affecting the kidney of the exposed fish. Significant increases in the serum creatinine and uric acid levels and severe pathological lesions were recorded in the renal tissue of PE-MPs (10 mg/L) and SLS (4 mg/L)-exposed groups. In addition, significantly higher fibrosis as well as hypoglycemia were observed in all the exposed groups compared to the control group. Nevertheless, the combined exposure to these substances revealed non-significant differences in the serum uric acid level and mild pathological lesions as well as lower fibrosis and hypoglycemia. In conclusion, PE-MPs and SLS are nephrotoxic for fish either singularly or in combination. Unexpectedly, an antagonistic effect in the form of lower nephrotoxicity was observed upon the combined exposure of 10 mg/L PE-MPs + 4 mg/L SLS might be due to some interaction between both substances that altered their toxicity.