Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic liver disease (NAFLD). Chronic impairment of lipid metabolism is closely related to alterations of the oxidant/antioxidant balance, which affect metabolism-related organelles, leading to cellular lipotoxicity, lipid peroxidation, chronic endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes stress pathways, leading to inflammation and fibrogenesis, contributing to the progression of non-alcoholic steatohepatitis (NASH). The antioxidant response, regulated by the Nrf2/ARE pathway, is a key component in this process and counteracts oxidative stress-induced damage, contributing to the restoration of normal lipid metabolism. Therefore, modulation of the antioxidant response emerges as an interesting target to prevent NAFLD development and progression. This review highlights the link between disturbed lipid metabolism and oxidative stress in the context of NAFLD. In addition, emerging potential therapies based on antioxidant effects and their likely molecular targets are discussed.