Introduction: Liver, main organ for biotransformation of drugs, during which most of the drugs which are lipophilic in nature are made hydrophilic by the biochemical processes in the liver cells resulting into water-soluble products which get excreted in urine or bile. Adverse drug reactions (ADRs) pertaining to liver, can be of mainly two types, predictable or dose dependent and idiosyncratic. To counter the oxidative stress and cellular damage, several antioxidant enzymes have been developed including superoxide dismutase (SOD), Glutathione peroxidase and catalase, that detoxify the reactive oxygen species and the cells contained endogenous antioxidants that scavenge the free radicals and reduces the cellular damage of which glutathione plays a major role. Synthesis of glutathione is regulated at the substrate level by cysteine, which is synthesized from homocysteine via the trans-sulfuration pathway N-Acetylcysteine used as a specific drug in the treatment of Paracetamol overdose, serves as a prodrug to L-Cysteine, which is a precursor to the antioxidant Glutathione. L-methionine, a precursor of L-cysteine, which is considered to have antioxidant activity, is found to be a precursor to glutathione as well. Methionine is particularly important in opposing the toxicity of free radicals generated by various toxins. Hence, supplementation of the same has been proposed to have a greater role in reducing the toxic effect on liver. The aim was to study the comparative hepatoprotective effect of orally administered DL-Methionine and N-Acetylcysteine on the liver injury induced by positive control Diclofenac Sodium. Materials and Methods: The healthy albino rats were grouped for the experimental study, in various groups (n=6). After overnight fasting, rats belonging to Group I Vehicle treated Group (n=6) were administered Distilled Water 10 ml/kg orally Group II to V were administered single oral dose concomitantly with Diclofenac sodium (96 mg/kg & 240 mg/kg p.o.) and DL-Methionine (700 mg/kg p.o. & 1400 mg/kg p.o.) respectively. Group VI and VII were administered single oral dose concomitantly with Diclofenac sodium (96 mg/kg & 240 mg/kg p.o.) and N-Acetylcysteine 450 mg/kg p.o., respectively. Serum samples from each rats were collected after 24-hours of post-treatment, to study the comparative effects of DL-Methionine and N-Acetylcysteine on the liver injury induced by positive control Diclofenac Sodium through Haemato-biochemical changes. Results: The vehicle-treated group showed no significant alteration in the level of liver function tests and liver morphology. On concomitant administration of DL-Methionine 700 mg/kg with Diclofenac sodium 96 mg/kg and 240 mg/kg it was observed that there occurred significant reduction (p < 0.001) in the serum SGOT and SGPT levels as compared to control and positive control group. The hepatoprotective effect of DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg on concomitant administration with positive control drug Diclofenac sodium 96 mg/kg were compared for their effect on serum SGPT levels and was observed that there was no statistically significant decrease in the levels of SGPT when compared between the two groups of hepatoprotective agents. The hepatoprotective effect of DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg on concomitant administration with positive control drug Diclofenac sodium 240 mg/kg, were compared for their effect on serum SGPT levels. It was observed that there was a significant reduction (p <0.05) in SGPT levels, with DL-Methionine 700 mg/kg and N-Acetylcysteine 450 mg/kg. However, in both the doses of DL-Methionine, there were no statistically significant changes in the Total Serum Bilirubin, serum Alkaline Phosphatase & serum Gamma-Glutamyl Transpeptidase (GGTP) levels. Conclusion: We have compared for the effectiveness of DL-Methionine and N-Acetylcysteine for their hepatoprotective effect against Diclofenac-induced hepatotoxicity, where we have observed, both DL-Methionine and N-Acetylcysteine reduces the serum transaminases levels, that were elevated due to the hepatotoxic effect of diclofenac sodium. However, there was no much of a difference of hepatoprotective effect of both DL-Methionine and N-Acetylcysteine. In summary, our present study reinforced the concept that hepatotoxicity induced by drug can be protected by administering NAC even in cases of non-paracetamol induced liver injury.