Bicyclol has been approved as an anti-inflammatory, hepatoprotective drug in China to treat various forms of hepatitis. However, the role of bicyclol in non-alcoholic fatty liver disease (NAFLD) is unknown. In this study, NAFLD model was established by feeding mice with high fat diet (HFD) for 16 weeks, and bicyclol (25 and 50 mg/kg) were orally administered for the last 4 weeks. Although bicyclol treatment did not change the body weight of mice, bicyclol administration significantly improved HFD-induced dyslipidemia, NAFLD activity score, hepatic apoptosis, systemic and hepatic inflammation, and liver fibrosis in the mice. Moreover, bicyclol treatment significantly inhibited HFD-induced activation of MAPKs and NF-κB signaling pathways that may mediate the inflammatory responses. Further in vitro studies showed that bicyclol pretreatment markedly ameliorated PA-induced inflammatory responses in human hepatocyte HL-7702 cells and mouse peritoneal macrophages through inhibiting MAPKs and NF-κB signaling pathways. These data indicated that bicyclol may have the potency to treat NAFLD by reducing inflammation.