Abstract Objective The objective of the current study is to investigate the protective effect of Solenostemma argel (S. argel) treatment on ethanol (EtOH)-induced hepatotoxicity in rat liver. Methods Forty adult male albino rats were divided into four groups as control, S. argel (100 mg/kg), EtOH (3 g/kg) and S. argel + EtOH groups. S. argel was given 1 h prior to EtOH by oral gavage for 28 days. Results The results showed that, administration of EtOH caused a significant decrease (p<0.05) in serum total protein and albumin, whereas ALT and AST and lipid peroxidation (LPO) were increased following EtOH treatment. S. argel treatment significantly (p<0.05) ameliorated the previous parameters. Protein carbonyl, reduced glutathione and LPO levels were significantly (p<0.05) increased along with glutathione-S-transferase activity was decreased (as markers of oxidative stress) in EtOH treated rat liver. Previous oxidative stress was attenuated significantly by S. argel treatment. Moreover, in EtOH group, tumor necrosis factor-α (TNF-α) and nitric oxide (NO) contents and cytochrome P450 2E1 activity were significantly increased in liver tissues showing oxidative organ damage. Co-administration of S. argel with EtOH significantly reversed the inflammation in rat livers. Conclusion S. argel had a hepatoprotective role against EtOH-induce oxidative stress and inflammation in rat liver.