Surgery-induced epidural fibrosis after laminectomy often results in poor clinical outcomes. Fibroblasts proliferation is considered to be one of the major causes of epidural fibrosis formation. Previously, there was no research about the effect of Homoharringtonine(HHT) on inhibiting fibroblast proliferation and reducing epidural fibrosis. Here, we performed in vitro and in vivo experiments to explore the effect of HHT on inhibiting fibroblast proliferation, inducing fibroblast apoptosis and preventing epidural fibrosis formation. In vitro, the effect of HHT on inhibiting fibroblasts was detected by CCK-8 assay. Besides, the effect of HHT on causing fibroblast apoptosis was investigated via Western blots, flow cytometry and TUNEL assay. Results suggested that HHT could inhibit fibroblasts proliferation and induce apoptosis. And the marker proteins of endoplasmic reticulum (ER) stress were also changed positively. In vivo, histological macroscopic assessment, hydroxyproline content analysis and histological staining were used to detect the effect of HHT on reducing epidural fibrosis. The results showed that HHT had positive suppressive effects on epidural fibrosis following laminectomy in rats. TUNEL assay in epidural tissue suggested that HHT could obviously induce fibroblasts apoptosis. Immunohistochemistry staining showed that the expression of two important ER stress markers(78-kDa glucose-regulated protein and C/EBP homologous protein) were also increased. In conclusion, this research showed that HHT could reduce epidural fibrosis formation after laminectomy, and the potential mechanism might through inhibiting fibroblasts proliferation and inducing fibroblasts apoptosis via ER stress signaling pathway. It might provide a novel agent for reducing epidural fibrosis after laminectomy surgery.