AbstractInterleukin (IL)‐25 is a cytokine that has previously been shown to have a protective role against nonalcoholic fatty liver disease (NAFLD), which is associated with the induction of M2 macrophage differentiation. However, the direct relationships between IL‐25 expression regulation, M2 induction and NAFLD remain unknown. In this study, we demonstrate that IL‐25 promotes hepatic macrophage differentiation into M2a macrophages both in vivo and in vitro via the IL‐13/STAT6 pathway. M2 macrophages that were differentiated in vitro were able to ameliorate high‐fat diet HFD‐induced hepatic steatosis. Furthermore, we found that IL‐25 treatment, both in vitro and in vivo, promotes direct binding of STAT6 to the IL‐25 gene promoter region. This binding of STAT6 in response to IL‐25 treatment also resulted in the increase of IL‐25 expression in hepatocytes. Together, these findings identify IL‐25 as a protective factor against HFD‐induced hepatic steatosis by inducing an increase of IL‐25 expression in hepatocytes and through promotion of M2a macrophage production.