Excessive fatty acid uptake-induced oxidative stress causes liver injury and the consecutive recruitment of inflammatory immune cells, thereby promoting the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Lycopene, the most effective singlet oxygen scavenger of the antioxidant carotenoids, has anti-inflammatory activity. Here, we investigated the preventive and therapeutic effects of lycopene in a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet. Lycopene alleviated excessive hepatic lipid accumulation and enhanced lipolysis, decreased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis, and subsequently reduced the recruitment of CD4+ and CD8+ T cells in the liver. Importantly, lycopene reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. In parallel, lycopene decreased LPS-/IFN-γ-/TNFα-induced M1 marker mRNA levels in peritoneal macrophages, as well as TGF-β1-induced expression of fibrogenic genes in a stellate cell line, in a dose-dependent manner. These results were associated with decreased oxidative stress in cells, which might be mediated by the expression of NADPH oxidase subunits. In summary, lycopene prevented and reversed lipotoxicity-induced inflammation and fibrosis in NASH mice by reducing oxidative stress. Therefore, it might be a novel and promising treatment for NASH.