Objective To explore the mechanism by which oridonin regulates the microRNA200c (miR-200c) / enhancer of zeste homolog 2 (EZH2) axis to inhibit the epithelial-mesenchymal transition (EMT) of melanoma cells (A375 cells). Methods The MTT method was used to detect the effect of Rubescensine A on the viability of A375 cells. A375 cells were divided into a control group, oridonin group, mimic control group, miR-200c mimic group, oridonin+inhibitor control group, and oridonin+miR-200c inhibitor group. qRT-PCR was used to detect the expression of miR-200c and EZH2 mRNA, Western blot was used to detect the expression of EZH2 and EMT-related proteins, adhesion test was used to detect the adhesiveness of A375 cells, Transwell test was used to detect the invasiveness and migration abilities of A375 cells, while a luciferase reporter gene experiment was used to detect the targeting relationship between miR-200c and EZH2, construct a nude mouse model of transplanted tumor to detect tumor quality. Finally, the expression of EMT-related proteins was analyzed immunohistochemically. Results The survival rate of A375 cells decreased significantly with increasing oridonin concentration in a dose-dependent manner (P<0.05). Since 40 μmol / L oridonin was close to the half inhibitory concentration, 40 μmol / L oridonin was selected for follow-up experiments. Compared with those in the control group, the expression levels of miR-200c and E-cadherin in A375 cells in the oridonin group and miR-200c mimic group increased significantly, while the expression levels of EZH2 mRNA and protein, neural cadherin ( N-cadherin), and Vimentin, number of migrating cells, number of invading cells, and number of adhering cells decreased significantly ( P< 0.05). Compared with the control group and the mimic control group, the expression level of EZH2 protein in the miR-200c mimics group was significantly decreased (P<0. 05), and the silencing of miR-200c could reverse the effect of oridonin on A375 cells. Compared with the levels in the control group, the tumor quality and expression levels of EZH2 mRNA, N-cadherin, and Vimentin were significantly decreased in the oridonin group, while the expression levels of miR-200c and E-cadherin were significantly increased ( P< 0.05). Moreover, compared with those in the oridonin group, the tumor quality and expression levels of EZH2 mRNA, N-cadherin and Vimentin in the oridonin+miR-200c inhibitor group were significantly increased, while the expression levels of miR-200c and E-cadherin were significantly decreased (P<0.05). Conclusions Oridonin may inhibit the EMT of A375 cells and tumor growth by promoting the miR-200c / EZH2 axis.