Glioblastoma multiforme (GBM) is one of the most deadly diseases affecting humans, and is often characterized by poor survival and by high resistance to chemotherapy and radiotherapy. Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of GBM following surgery. Although TMZ may restrain GBM growth, TMZ resistance is also common and accounts for numerous cases of treatment failure. Studies indicate that aberrant miRNA expression is associated with hallmark malignant properties of GBM. Thus, miRNA-based anticancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies to enhance the efficacy of chemotherapy agents. In the present study, we demonstrated that the expression of miR-128 and miR-149 was downregulated in glioblastoma, and their overexpression inhibited the invasion of glioblastoma cells by targeting Rap1B-mediated cytoskeletal and related molecular alterations. Moreover, miR-128 and miR-149 enhanced the chemosensitivity of glioblastoma cells to TMZ.