Sodium nitrite (NaNO₂) is important antimicrobial, flavoring, coloring and preservative agent in meat and fish product. However, nitrite may cause methemoglobinemia and other illness, and may react with certain amines to form carcinogenic nitrosamines. The study aimed to evaluate the efficacy of grape seeds extract (GSE) as a potential novel and useful strategy for the modulation of oxidative stress and toxicity induced by NaNo₂ in male rats. Sodium nitrite was used at two dose levels 1 and 2g/L and orally administrated to rats in drinking water for 4 and 8 weeks. Ingestion of NaNO₂, resulted in significant time and dose- dependent reduction in RBCs count, WBCs count, hemoglobin (Hb) content, serum albumin and total protein (TP), plasma reduced glutathione (GSH), glutathione -S- transferase (GST), superoxide dismutase (SOD) contents in the treated rats. whereas, blood methemoglobin (MetHb), serum alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), creatinine, urea, triglycerides, total cholesterol and  lipid peroxidation product (malondialdehyde, MDA) were significantly increased in dose and time dependant manner after implication of this preservative. Hyperglycemia was observed in NaNO₂ ingested rats. Moreover, histopathological examination of NaNO₂ treated rats at the end of experiment revealed marked alterations in liver, kidneys, brain, heart, lung and testes. The degree of severity of noted lesions increased with increase of administrated dose. Fortunately, synergistic administration of ethanolic GSE (150 mg/kg body weight (B.W)/day) and NaNO₂ resulted in significant amelioration of negative effect of NaNO₂ on the investigated biochemical parameters and improvement of investigated antioxidant especially with low NaNO₂ dose and longer time. Moreover, GSE administration was able to protect most of tested organs against low NaNO₂ dose and minimize the damage induced by high NaNO₂ dose. It was concluded that GSE supplementation could be considered as a promising antioxidant in reducing oxidative stress and toxicity of NaNO₂.