Background: The early treatment of liver disease, hepatic inflammation, could prevent the progression to severe fibrogenesis and finally HCC. Natural products that could provide hepatoprotective effects against xenobiotics/drugs are urgently needed. Objective: this study investigates the safety and hepatoprotective activity of eugenol, hesperidin and Lepidium sativum (LP) alkaloids in rats with thioacetamide (TAA)-induced hepatotoxicity. Materials and Methods: TAA-intoxicated rats were given eugenol, hesperidin or LP in oral doses of 10.7, 40 and 400 mg/kg/day respectively for 4 weeks. Liver function, inflammatory and oxidative stress markers as well as immunohistopathological changes were assessed. Results: Compared to TAA-intoxicated group, eugenol normalized ALT and AST, however, hesperidin and LP decreased (P<0.05) their values by 28.41% & 23.82% and 47.78% & 32.59%, respectively. Also, eugenol and hesperidin normalized TNF-α, IL-6 and INF-γ, meanwhile, LP lowered their values (P<0.05) by 55.24%, 9.93% and 34.03% respectively. Moreover, eugenol and hesperidin decreased NF-кB and CYP2E1, with an increase in caspase-3 positive cells as well as SOD and GSH hepatic levels. Meanwhile, treatment with LP failed to decrease NF-кB and caused severe apoptosis. Eugenol and hesperidin-treated rats showed almost normal hepatic architecture, mild portal tract inflammation and minimal degrees of necrosis. LP as well mitigated liver tissue damage and inflammation as noted by less inflammatory infiltration and hydropic degeneration. Concerning MTT cytotoxicty assay on primary isolated hepatocytes, hesperidin was safe at 24 h and 48 h, meanwhile, eugenol was safe only at 24 h in concentrations from 5 to 100 µg/ml, yet it was cytotoxic at all concentrations at 48 h. However, LP showed cytotoxic effects at both 24 h and 48 h. Conclusion: Hesperidin could be a promising hepatoprotective agent evidenced by the biochemical, histopathological and immunohistochemical findings. Whereas, eugenol and LP showed cytotoxic effects, so these compounds could not recommended to be used as hepatoprotective agents.