Background and purpose: Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor (Nrf)2, which induces anti-oxidative-associated genes. CDDO-Me is known to exert protective effects against chronic inflammatory diseases in the kidney and lungs. However, its pharmacological effects on non-alcoholic steatohepatitis (NASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced NASH mouse model, and elucidated its pharmacological mechanisms using RNA-seq analysis. Experimental approach: CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet, and histological, biochemical, and transcriptome analyses were performed on the livers of mice that developed NASH. Key results: CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly improved the symptoms of NASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that leads to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligand (CCL)3 and CCL4 in the downstream of NF-B, which are associated with the recruitment of macrophages expressing CC chemokine receptor (CCR)1 and CCR5, were released into blood in NASH mice. In contrast, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages. Conclusions and Implications: Overall, this study revealed the potent hepatoprotective effect of CDDO-Me in a NASH mouse model, and demonstrated that its pharmacological effects were closely associated with the reduction of macrophage infiltration through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects.