Excessive hepatic lipid accumulation promotes the activation of macrophage/Kupffer cells, resulting in exacerbation of insulin resistance and nonalcoholic steatohepatitis (NASH). Pirfenidone is an antifibrotic agent used in the treatment of pulmonary fibrosis. Pirfenidone also suppresses bleomycin-induced increases in the pulmonary influx of T cells and macrophages. However, less attention has been focused on its anti-inflammatory effects. Here, we investigated the effect of pirfenidone in a lipotoxicity-induced NASH model. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet with or without 0.2% pirfenidone. After 12 weeks, pirfenidone treatment reduced hepatic triglyceride, cholesterol, and NEFA levels, as well as lipid peroxidation, which was assessed by TBARS. Pirfenidone improved glucose intolerance and hyperinsulinemia in the CL group and enhanced the insulin signal, assessed by IRβ and Akt phosphorylation, in the liver, which is associated with the attenuation of MAPK (ERK/p38MAPK) and NF-kB activation. Flow cytometry analysis revealed that pirfenidone reduced total hepatic macrophages, particularly CD11c+CD206−(M1), whereas it increased CD11c-CD206+(M2), with subsequent reduction of CD4+ and CD8+ T-cell contents, which contributed to the improvement of insulin resistance and steatohepatitis. Moreover, pirfenidone downregulated LPS-induced M1 marker mRNA expression in RAW264.7 macrophages but augmented IL-4-induced M2 marker mRNA expression in a dose-dependent manner. Additionally, pirfenidone reduced the activation of hepatic stellate cells and inhibited fibrosis, lowering hydroxyproline content by 40% (p < 0.05). Importantly, pirfenidone reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing advanced NASH. In conclusion, pirfenidone might be a novel and promising treatment for NASH.