Activation of hepatic stellate cells (HSCs) is a central event in the pathogenesis of liver fibrosis and is often accompanied by the disappearance of lipid droplets (LDs). Although interference with LD metabolism can effectively reverse the activation of HSCs, there is currently no effective therapy for liver fibrosis. Our previous evidence indicates that long non-coding RNA (lncRNA)-H19 plays an essential role in LD metabolism of HSC. In this study, we investigated the potential molecular mechanism of dihydroartemisinin (DHA) inhibits LD metabolism and liver fibrosis by regulating H19-AMPK pathway. We found that DHA restores LDs content in activated HSCs via reducing the transcription of H19 driven by hypoxia inducible factor 1 subunit alpha (HIF1α) and inhibiting the lipid oxidation signal mediated by AMP-activated protein kinase (AMPK) phosphorylation. In vivo experiments, we have proved that DHA reduced the deposition of extracellular matrix (ECM) and reduce the level of liver fibrosis in CCl-induced liver fibrosis of mice. In summary, our results emphasize the importance of H19 in liver fibrosis and the potential of DHA to regulate H19 to treat liver fibrosis, providing a new direction for the prevention and treatment of liver fibrosis.