The aimof this studywas to examine the protective effects of Nigella sativa (N. sativa) on 4-Nonylphenol-induced nephrotoxicity in Clarias gariepinus. 30 fishes were divided into five groups: control, 4-nonylphenol-treated, 1% N. sativa treated, 2.5% N. sativa treated, and 5% N. sativa treated. N. sativa and 4-Nonylphenol were given for 3weeks. 4-NP and 4-NP-N. sativa treated fishes were comparedwith the control group. Kidney histology, immunochemistry, and electron microscope were assessed after 4-NP exposure. In the African catfish, 4-NP is mainly excreted through the kidney causing nephrotoxicity. Our results showed that 4-NP administration significantly disturbed the kidney structure and function. 4-NP treated fishes showed dilated glomerular vessels, fewer glomerular cells content, decreased expressions of glomerular proteins, and increased level of autophagy compared to control group (P b 0.05). As N. sativa has different immunological and pharmacological effects such as anti-apoptotic and anti-oxidant, therefore, the administration of N. sativawith 4-Nonylphenol significantly minimize the nephrotoxic effect of 4-NP and maintain the normal kidney structure and function. Our novel study demonstrated for the first time that N. sativa could protect the kidney against 4-NP induced-nephrotoxicity.