Nonalcoholic fatty liver disease (NAFLD) occurs due to lipid metabolic disorders, which is associated with hepatic oxidative stress and inflammation. There is no definitive drug treatment for this disease. Accordingly, the present study aimed to evaluate the effects of dimethyl fumarate (DMF) as one of the superior effective drugs that induces a transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) on development of NAFLD in mice. The metabolic disturbance in High-fat diet (HFD)-treated animals was associated with hyperlipidemia, increased activity levels of hepatic enzymes in serum, hyperglycemia, hyperinsulinemia, oxidative stress and inflammation. DMF supplementation had anti-inflammatory, antioxidant, anti-lipogenic and molecular compatibility effects induced by HFD in mice. In comparison to the HFD group, the DMF therapy could significantly suppress the sterol regulatory element binding protein-1 c (SREBP-1c) gene and protein levels, as well as upregulate the Nrf2 gene and protein levels. Additionally, the anti-inflammatory activity was observed for the DMF by inhibiting the nuclear factor kappa B (NF-κB) level. DMF reduces the development of NAFLD induced by HFD in mice through the modulation of transcription factors Nrf2, SREBP-1c and NF-κB. Thus, DMF can be considered as an effective candidate in the treatment of human NAFLD.