Glioblastoma Multiforme (GBM) remains as one of the most aggressive and lethal cancer types, often resulting in poor prognosis. Currently, Temozolomide (TMZ) is the standard chemotherapy for combating GBM. However, GBM’s upregulation of O-6-Methylguanine-DNA Methyltransferase (MGMT) mitigates the alkylating effects of TMZ treatment, generating a dire new need for novel or adjuvant therapy. U138MG is a TMZ-resistant GBM cell line used for the development of new chemotherapy. Here, we investigated whether inhibition of proton sensing GPR68 would decrease MGMT expression and sensitize U138MG cells to TMZ treatment. Using various genetic, protein, and cell-based assays we determined that inhibition of GPR68 may be decreasing MGMT protein expression and sensitizing U138MG to TMZ via the Gq/NFkB pathway. Furthermore, we identified that co-administration of TMZ and OGM resulted in a synergistic decrease in cell growth compared to OGM treatment alone.