Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor worldwide. Despite the advances made in treatment and research, the median survival time for GBM patients remains <1.5 years, providing impetus for the identification of potential novel therapeutic target genes to improve GBM treatment. The deubiquitinating enzyme ubiquitin specific peptidase 15 (USP15) has emerged as a pro-oncogenic factor; however, its function in GBM has yet to be fully elucidated. The present study sought to determine whether or not USP15 is implicated in GBM cell invasion and proliferation. Following the depletion of USP15 in U87-MG and U251-MG cells by lentivirus-mediated USP15 short hairpin RNA (shRNA), the invasiveness of glioma cells was investigated. The results of the present study demonstrated that glioma cells expressing USP15 shRNA exhibited significantly lower invasiveness than cells that did not express USP15 shRNA. Additionally, USP15 depletion led to the upregulation of E-cadherin and downregulation of the mesenchymal markers, N-cadherin and vimentin. Furthermore, the influence of USP15 on glioma cell proliferation was investigated and depletion of USP15 resulted in a marked reduction in cell proliferation. Taken together, the findings of the present study clearly support the hypothesis that USP15 renders GBM cells capable of invasion and proliferation.