Acetaminophen (APAP) is one of the most frequently used analgesics and antipyretics worldwide, however, an overdose of paracetamol is a leading cause of hepato-renal injury. N-acetylcysteine (NAC) has been used as a remedy for paracetamol-induced toxicity, however several adverse effects of long-term use of NAC have been reported. Therefore, we assessed the ameliorating effect of lacteol forte® and vitamin B12 alone or in combination against APAP-induced hepatorenal injury in rats and compare it with that of NAC. Fife groups of rats were given APAP (400 mg/kg BW, i.p.), while the control group was treated only with 0.9% saline. Treatment with NAC, lacteal forte®, and vitamin B12 was done 24hrs after APAP. Serum biochemical parameters related to liver and kidney injury, including, AST, ALT, HDL, urea, and creatinine were estimated in all groups, hepatic and renal lipid peroxidation, and antioxidant biomarker levels were also determined. The expression of the tumor necrosis factor (TNF- α), TNFR-1, COX-1 and COX-2 genes was investigated. Finally, sections of the liver and kidney of all rats were examined for any histopathological changes. Results: Compared to control rats, APAP induced acute hepatic and renal toxicity manifested by significant increases in serum biochemical parameters related to liver and kidney injuries. Also, APAP significantly increased hepatic, and renal lipid peroxidation and decreased antioxidant biomarker levels. APAP upregulated the expression of TNF-α and TNFR-1 genes, while it downregulated the expression of COX-1 and COX-2 genes. It also produced marked histopathological lesions of liver and kidney. The test treatment with lacteal forte and vitamin B12 combination had improved serum parameters and gene expression, enhanced endogenous antioxidant status, reduced lipid peroxidation, and histopathological lesions in a comparable fashion to that of NAC effects. Conclusions: Our data confirmed that treatment with vitamin B12 and lacteal forte® combination has exerted potent antioxidant and free radical-scavenging activities comparable to that NAC. Suggesting that combination of vitamin B1 and lacteal forte® may be considered a safer alternative to NAC in ameliorating APAP induced toxicities. More research will be required to estimate the level of toxic metabolite, NAPQI, to determine the actual mode of action of these medications in protecting against APAP toxicity.