To study the effect of Clobetasol propionate (Clo) on the differentiation of nasal mesenchymal stem cells (EMSCs) into neuron-like cells. Methods: EMSCs were isolated and cultured by the adherent screening method, and the EMSCs amplified in vitro were identified by immunofluorescence. The effect of Clo on the proliferation of EMSCs was examined by MTT assay. Induced neuroblast-like cells were divided into the Clo group, Sonic hedgehog (SHH) group, and control group. All-trans retinoic acid (ATRA) was used to induce differentiation into neuron-like cells. Changes in cell morphology were observed under inverted microscope, and detection of neuronal cell-associated proteins was accomplished by immunohistochemistry and immunoblot methods. Results: EMSCs isolated and cultured in vitro displayed high expression levels of mesenchymal and neural stem cell markers vimentin and nestin. After induction of EMSCs into neuroblast-like cells for 7 days, the EMSCs in the Clo and SHH groups showed bipolar and multipolar typical neuron-like cell morphology and high expression of neuronal cell-associated proteins. At the same time, the expression levels of SHH and SMO in the EMSCs of the Clo group were significantly higher than those of the control group, and there was no significant difference compared with that of the SHH group (P>0.05). Data showed that Clo could promote the secretion of endogenous brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) by EMSCs. Conclusion: Clo can promote the differentiation of EMSCs into neuron-like cells by activating the SHH signaling pathway and up-regulating the levels of endogenous neurotrophic factors.