Objective To investigate the effect of mcroiRNA-378-5p (miR-378-5p) on the sensitivity of TMZ chemotherapy. Methods The effect of miR-378-5p on the growth inhibition of glioma cells induced by TMZ were detected by CCK-8. TMZ induced apoptosis were analyzed by flow cytometry. RT-PCR was used to detect the mRNA levels of Bcl-2, Bax, and MGMT in glioma cells. The protein expression of MGMT were measured by WB. Results Overexpression miR-378-5p significantly inhibited the growth inhibition and apoptosis of glioma cells induced by TMZ. Then, miR-378-5p significantly upregulated the Bcl-2/Bax ratio. RT-PCR and WB results showed that miR-378-5p increased the mRNA and protein expression of MGMT. Conclusion miR-378-5p may inhibit TMZ induced apoptosis and reduce the sensitivity of TMZ chemotherapy by increasing MGMT expression