The present study investigated the mitigative effect of Vitex negundo against sodium fluoride (NaF) induced cardio and nephrotoxicity. The hydroalcoholic extract of Vitex negundo leaves (HAEVNL) was prepared by the maceration method. Group I, Group II, and Group III served as normal, toxic, and plant control groups in the treatment schedule. Group IV and V (200 and 400 mg/kg b.wt, p.o) served as treatment groups. Group II, IV, and V treated with NaF (100ppm) through drinking water for 4 weeks. Cardiac and kidney parameters such as LDH, CK-MB, Lipid profile, Creatinine, Urea, and Uric acid were estimated. The heart and kidney tissues LPO, GSH, SOD, and CAT levels and histopathological studies were performed. Phytochemical investigation showed the alkaloids, saponins, phytosterols, flavonoids, phenols, and tannins. Rats administered with NaF have demonstrated a significant rise in the LDH, CK-MB, TC, TG, LDL-C, VLDL-C, Creatinine, Urea, and Uric acid. Tissue LPO levels increased while there was a significant decrease in serum HDL-C and tissue SOD, GSH, and CAT levels. Treatment with HAEVNL showed effective recovery against NaF-induced cardio and nephrotoxicity. The histopathological evaluation also added to the benefits of the Vitex negundo leaves. The study concluded that Vitex negundo leaf extract showed a significant antioxidant and mitigative effect against fluoride- induced cardio and nephrotoxicity in rats.