Aims: This study was carried out to evaluate the hepatoprotective effect of Platycodon grandiflorum (PG) in ethanol (EtOH)-induced liver damage. Methods and Results: PG treatment (both the total extract and saponin fraction) significantly blocked EtOH-induced oxidative stress through the preservation of activities of antioxidant enzymes in HepG2 cells. Furthermore, while the administration of EtOH to C57BL/6 mice for 6 weeks induced liver damage, along with a significant increase in plasma glutamic oxalacetic transaminase, glutamic pyruvic transaminase, hepatic triglyceride and thiobarbituric acid reactive substance levels, PG treatment significantly decreased glutamic oxalacetic transaminase, glutamic pyruvic transaminase, hepatic triglyceride and thiobarbituric acid reactive substance levels compared with the EtOH-treated control group (p < 0.05). Histological observation by hematoxylin-eosin and oil red O staining in the liver showed more effective inhibition of lipid accumulation in PG-treated groups, as compared to the EtOH-treated control group. Additionally, PG treatments appeared to enhance the activities of superoxide dismutase and catalase in the liver (p < 0.05). Conclusion: These results suggest that PG has a protective effect against EtOH-induced oxidative damage, possibly by inhibition of lipid accumulation and peroxidation through the enhancement of the antioxidant defense system. PG might be useful as a therapeutically potent natural ingredient for the prevention of chronic EtOH-induced oxidative stress and liver damage.