Paracetamol is a widely used analgesic and antipyretic drug, but at high doses it leads to undesirable side effects, mainly hepatotoxicity. The hepatoprotective effect of caffeic acid has been previously reported, however the mechanism of this protective effect is not fully explored. The current study aimed to investigate the therapeutic potential of caffeic acid vs. silymarin in paracetamol-induced hepatic damage. To better understand the mechanisms by which  these phenolic compounds confer their protective effects, parameters of lipid peroxidation, hepatic inflammation and neutrophils infiltration were evaluated. In addition, liver toxicity markers and hepatic antioxidants (enzymatic as well as non-enzymatic) were measured. Daily administration of paracetamol (700 mg/kg, p.o.) caused hepatic injury that was manifested as increased hepatic levels of malonaldehyde (MDA), tumor necrosis factor-alpha (TNF-α) and heme oxygenase (HO-1) with marked increase in myeloperoxidase (MPO) activity, depletion of liver reduced glutathione, and diminished catalase and super-oxide dismutase (SOD) activities. Furthermore, serum liver enzymes (ALT, AST, GGT) were significantly increased along with hepatocellular degeneration and steatosis. Co-treatment with caffeic acid or silymarin alleviated paracetamol-induced oxidative stress, blunted TNF-α levels and MPO activity, while enhanced HO-1 levels with restoration of antioxidant enzymes activities. This was accompanied by normalization of liver transaminases and improvement of hepatic architecture. Interestingly, the effect of caffeic acid on HO-1, TNF-α, and MPO was more prominent when compared to silymarin. The present study provide an evidence on the multiple mechanisms by which caffeic acid as well as silymarin grant their hepatoprotective activities mainly through the induction of HO-1 in addition to the reduction of oxidative stress burden in hepatocytes. The powerful anti-oxidant effect was accompanied by a significant anti-inflammatory activity.