ABSTRACT Introduction: Oxidative stress underlies the pathophysiology of various etiologies of chronic liver disease and contributes to the development of hepatocarcinogenesis. Areas covered: This review focuses on the impact of oxidative stress in various etiologies of chronic liver disease such as alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection. The efficacy of antioxidants in laboratory, animal, and clinical studies in chronic liver disease is also reviewed. Expert opinion: Currently, there are limited targeted pharmacotherapeutics for NASH and no pharmacotherapeutics for ALD and antioxidant supplementation may be useful in these conditions to improve liver function and reverse fibrosis. Antioxidants may also be used in patients with HBV or HCV infection to supplement antiviral therapies. Specific genotypes of antioxidant and prooxidant genes render patients more susceptible to liver cirrhosis and hepatocellular carcinoma while other individual characteristics like age, genotype, and metabolomic profiling can influence the efficacy of antioxidants on CLD. More research needs to be done to establish the safety, efficacy, and dosage of antioxidants and to establish the ideal patient profile that will benefit the most from antioxidant treatment.