Drug induced liver injury (DILI) leads to acute hepatitis in 10%, liver failure, and death in 30%. One of the major drugs causing DILI is Anti-tuberculous drugs and since tuberculosis is affecting 1/3rd of the total world population, their use is quite common. Use of Isoniazid (INH) is limited owing to hepatotoxicity following the stress produced by oxidative species. Silymarin has hepatoprotective potential because of anti-oxidant property. N-Acetylcysteine (NAC) on the other hand triggers the cellular protective mechanisms by replenishing glutathione in the cells. The main aim of this study was to compare the hepatoprotective activity of Silymarin and NAC against INH induced toxicity. Total 50 BALB/C mice were sorted into a total of 5 groups, with 10 mice in each group for 2 weeks by random sampling.  Control group was administered distilled water through I/P route daily. The INH group was administered I/P 100 mg/kg INH daily. The INH/Silymarin group was administered 150 mg/kg INH and 50 mg/kg Silymarin I/P daily. The INH/NAC group was administered 150mg/kg INH and 300mg/kg of NAC I/P daily. The INH/NAC/silymarin group was administered 150mg/kg INH, 300mg/kg of NAC and 50mg/kg of silymarin I/P daily. On day 14, the dissection of all the mice was done. Liver function tests were performed and histopathology was done. Both NAC and Silymarin demonstrated hepatoprotection that was statistically similar. However, the mice of silymarin group looked weak and less active and six dies within 5-8 days after the end of the experimental doses of the drugs.