Nonylphenol (NP) is a widespread contaminant in the ecosystem. Zinc is an essential trace element with many physiological activities. The existing study aimed to examine the possible favorable role of zinc sulfate against the immunosuppressive, hepatotoxic and nephrotoxic effects of NP in Oreochromis niloticus (O. niloticus). Two hundred and twenty-five tilapia fish were categorized into control, vehicle control, zinc sulfate (0.5 mg/L water), NP (50 μg/L water), and zinc sulfate + NP groups with 3 weeks period of exposure. Selective liver and kidney damaging byproducts, immunological, oxidative stress, lipid peroxidation, hematological, and inflammatory biomarkers were monitored as well as histopathological examinations were performed. The results revealed that NP induced hemolytic anemia, leukocytosis, hyperbilirubinemia, hyponatremia, hyperkalemia, azotemia, hyperproteinemia, hypoalbuminemia, hyper alpha1-globulinemia, hyper alpha2- and beta-globulinemia, and hypo gammaglobulinemia. Also, significantly elevated levels of ALT, AST, LDH, ammonia, cholesterol, creatinine, MDA, MPO, and TNF-alpha were recorded. Meanwhile, ALP, IgM, complement3, and NO levels together with lysozyme activity were significantly declined. Additionally, damage of hepatic and renal structural with splenic lymphoid depletion was also noted. On the contrast, Addition of zinc sulfate into the water restored the disturbances in most of those indicators elicited by NP. It is concluded that zinc sulfate has ameliorative action against hematotoxic, hepatotoxic, nephrotoxic, and immunosuppressive impacts of NP in Nile tilapia fish.