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Nonylphenol (NP) is a common toxicant that constitutes a potential hazard to the aquatic system. This study assessed the protective role of Salvia officinalis leaves powder (SOLP) against NP toxicity. We addressed mortalities, growth retardation, hepato-renal dysfunction, immune-antioxidant suppression, histopathological degeneration, and gene down-regulation induced by NP-toxicity. And the potential activity of SOLP against these negative impacts in Mirror carp (Cyprinus carpio var specularis). Acute toxicity assay (static 96-h) was primarily performed to investigate the 96-h LC50 of NP in C. carpio and it was recorded at 1.01 mg/L reckoned by Finney probit analysis. Fish (N = 240) were assigned to 4 treatments for 2 months. The first (control) and the second (SOLP) groups were fed on basal diets that were enriched with 0.0 and 4 g/kg of diet SOLP without NP exposure. The third (NP) and fourth (SOLP+NP) groups were provided with the same diets plus exposed to 1/10 of the 96 h-LC50 of NP (0.1 mg/L). The outcomes revealed that NP induced higher mortalities (46), significantly (p < 0.05) reduced growth, serum immune (nitric oxide and immunoglobulin M), and antioxidants (glutathione peroxidase and catalase) values. Moreover, down-regulation of immune-related genes (interleukin 6 and tumor necrosis factor-alpha) in the head kidney, and gills was observed in the NP group. However, noticeable augmented levels of serum oxidant (malondialdehyde), liver enzymes (Alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase); and kidney biomarkers (creatinine and urea) were recorded in NP group. Extensive pathology revealed that NP induced damage to hepatocytes and renal epithelium and mononuclear cells infiltrations in hepato-renal tissues. Dietary intervention with SOLP reduced mortalities (20 %), restored the reduction in the growth and biochemical indicators, and recovered the histopathology, and gene down-regulation produced by NP. Accordingly, the current study recommended SOLP as a valuable dietary additive in aquaculture owing to its mitigating impacts against NP by improving growth and immune-antioxidant status and regenerating the histological structure with a better gene expression.