Background: An overdose of paracetamol is a frequent reason for liver and renal 24 toxicity and possible death and curcumin has hepatoprotective properties against liver 25 damage. The exact mechanism of such protection is not clear. Therefore, this study 26 was conducted to examine the molecular levels of the protective effect of curcumin on 27 paracetamol overdose induced hepatic toxicity in rats. Male Wistar rats were allocated 28 into 4 groups. Control group, administered corn oil; curcumin group, administered 29 curcumin (400 mg/kg BW daily intra-gastric) dissolved in corn oil; paracetamol 30 group, administered corn oil with a single dose of paracetamol (500 mg/kg BW intra- 31 gastric) and protective group, administered curcumin with a single dose of 32 paracetamol. Curcumin was administered for 7 successive days, while paracetamol 33 was administered at day six of treatment. Blood and liver tissues were collected for 34 biochemical, histopathological, immunohistochemical and molecular examination. 35 Results: Serum analysis revealed an alteration in parameters of kidney and liver. A 36 decrease in the antioxidant activity of liver was recorded in paracetamol group while 37 curcumin administration restored it. Histopathological findings showed an extensive 38 coagulative necrosis in hepatocytes together with massive neutrophilic and 39 lymphocytic infiltration. Immunostaining of liver matrix metalloproteinase-8 (MMP- 40 8) in paracetamol administered rats showed an increase in MMP-8 expression in the 41 area of coagulative necrosis surrounding the central vein of hepatic lobules. Curcumin 42 administration decreased MMP-8 expression in liver of paracetamol administered rats. 43 Gene expression measurements revealed that paracetamol decreased the expression of 44 antioxidant genes and increased the expression of interleukin-1b (IL-1b), IL-8, tumor 45 necrosis factor-a (TNF-a) and acute phase proteins. Curcumin administration 46 3 ameliorated paracetamol-induced alterations in genes expression of antioxidant and 47 inflammatory cytokines. 48 Conclusion: The results clarified the strong protective effect of curcumin on 49 paracetamol induced hepatic toxicity in rats at the immunohistochemical and 50 molecular levels.