Objective To investigate the effect of microRNA (miRNA) 217 on endoplasmic reticulum stress-mediated autophagy and apoptosis in oral cancer cells and its molecular mechanism. Methods Human oral cancer cells and human normal oral keratinocytes were cultured. The expression levels of miR-217 and high mobility group A2 (HMGA2) in cells were detected by real-time quantitative polymerase chain reaction (RT-qPCR).The human oral cancer cell line SAS was divided into 4 groups: control group, miR-NC group, miR-217 mimic group and miR-217 mimic+4-PBA group, after transfection by liposome method and treatment with endoplasmic reticulum stress inhibitor 4-phenylbutyric acid. The flow cytometry was used to detect cell apoptosis rate. The Hoechst33342 staining was used to observe cell apoptosis. The cell immunofluorescence staining was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3) in cells. Western blot was used to determine the expression levels of autophagy-related proteins LC3I, LC3II and Beclin-1 in cells. RT-qPCR and Western Blot were used to determine the expression levels of intracellular endoplasmic reticulum stress-related molecules CCAAT/enhancer-binding protein homologous protein (CHOP), glucose-regulated protein 78 (GRP78) and aspartate proteolytic enzyme-12 (Caspase-12). The targeting effect of miR-217 on HGMA2 was verified by dual-luciferase reporter gene detection experiments and Western Blot. 〖WTHZ〗Results Compared with human normal oral keratinocytes HNOK, the relative expression of miR-217 was down-regulated and the relative expression of HMGA2 was up-regulated in human oral cancer cells HSC3, SAS, SCC15 and FaDu (P<0.05). Compared with the control group, the apoptosis rate of SAS cells in the miR-217 mimic group increased, there were a large number of apoptotic cells with bright blue and high fluorescence, the fluorescence intensity of LC3 increased, the ratio of LC3-II/LC3-I and Beclin-1 protein increased, and the relative expression levels of GRP78, CHOP, Caspase-12 mRNA and protein were up-regulated (P<0.05). Compared with the miR-217 mimic group, the apoptotic rate of SAS cells in the miR-217 mimic+4-PBA group decreased, the apoptotic cells with bright blue and high fluorescence decreased significantly, the LC3 fluorescence intensity decreased, the ratio of LC3-II/LC3-I and the relative expression of Beclin-1 protein were both down-regulated, the relative mRNA and protein expressions of GRP78, CHOP and Caspase-12 were also down-regulated (P<0.05). HMGA2 and miR-217 had base complementation in specific regions, and miR-217 targets and negatively regulates HGMA2 expression. Conclusion miR-217 may induce autophagy and death of oral cancer cells by promoting the endoplasmic reticulum stress pathway, and its mechanism may be related to the negative regulation of HMGA2 expression.