4-Nonylphenol (4-NP) is a nephrotoxic substance that is highly prevalent in aquatic environments. Nigella sativa seed (NSS) has many biological activities and is widely used throughout the world as a medicinal product. Therefore, in the present study, we investigated the cytoprotective effect of NSS on 4- NP-induced renal damage in African catfish (Clarias gariepinus). Thirty fish were divided into five equal groups: an untreated control group and four groups that were challenged with 4-NP at a dose of 0.1 mg L1 of aquarium water and fed a basal diet supplemented with 0%, 1%, 2.5%, and 5% NSS, respectively, for 3 weeks. Histological, histochemical, and ultrastructural features of the kidney were then assessed as biomarkers for renal tissue damage. Our results confirmed that 4-NP was a potent cytotoxic agent for the kidney tissue and induced renal damage, with 4-NP-intoxicated fish showing necrosis in the epithelial cells of the renal corpuscles, renal proximal convoluted tubules, and intertubular hematopoietic tissue, as well as loss of or a decrease in microvilli, a decrease in mitochondria, and an increase in the lysosomes in the epithelial cells of the proximal convoluted tubules. The kidneys of 4-NP-intoxicated fish also showed increased numbers of Perls’ Prussian blue-positive melanomacrophage centers and intraepithelial T-lymphocytes in the proximal convoluted tubules and plasma cells. The administration of NSS to 4-NP-challenged fish significantly minimized the cytotoxic effect of 4-NP, maintaining the normal kidney structure, with concentrations of 2.5% and 5% of feed being most effective for protecting the kidney against 4-NP-induced renal damage.