Oxidative stress is closely related to metabolic disorders, which can lead to various diseases. Nuclear factor E2-related factor 2 (Nrf2) is a central regulator of oxidative stress. Sodium butyrate (NaB) has been shown to alleviate oxidative stress and insulin resistance, yet how Nrf2 is involved in the action of NaB remains unclear. In this study, rats were rendered obese by feeding a high-fat diet for 9 weeks. NaB (300 mg/kg), which was gavaged every 2 days for 7 weeks, significantly alleviated high-fat diet-induced oxidative stress and insulin resistance. Additionally, the insulin signaling pathway in the liver was activated by NaB, associated with significant activation of Nrf2, superoxide dismutase and glutathione. Furthermore, hepatic up-regulation of Nrf2 in NaB-treated rats was associated with reduced protein content of histone deacetylase 1 and increased histone H3 acetyl K9 (H3K9Ac) modification on the Nrf2 promoter. The actions of NaB were completely abolished when Nrf2 was knocked down in vitro. Taken together, NaB acts as a histone deacetylase inhibitor to up-regulate Nrf2 expression with enhanced H3K9Ac modification on its promoter. NaB-induced Nrf2 activation stimulates transcription of downstream antioxidant enzymes, thus contributing to the amelioration of high-fat diet-induced oxidative stress and insulin resistance.