Liver fibrosis, a major cause of end‐stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low‐ and high‐molecular‐weight FGF2 (namely, FGF2^lmw and FGF2^hmw, respectively) in hepatic fibrogenesis using a CCl₄‐induced mouse liver fibrosis model. FGF2^hmw displayed a robust increase in CCl₄‐induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2^lmw exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2^lmw potently ameliorated CCl₄‐induced liver fibrosis. Mechanistically, we showed that FGF2^lmw treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down‐regulation of Delta‐like 1 expression through the p38 mitogen‐activated protein kinase pathway. Conclusion: FGF2^lmw and FGF2^hmw have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2^lmw administration, which may provide a novel approach to treat chronic liver diseases. (Hepatology 2015;61:1708–1720)