Background: Repurposing non-cancer drugs may represent a new source of novel therapies for glioblastoma (GBM). Memantine, mefloquine, and metformin have putative anticancer activity potentially relevant to gliomas. The aim of this phase I factorial study was to determine the maximum tolerated doses (MTD) of combinations of these agents with temozolomide (TMZ) for newly diagnosed GBM. Methods: Adults (≥18 years of age) with newly diagnosed GBM who received chemoradiation with TMZ, with no progressive disease on post-treatment imaging, were eligible. The patients were sequentially enrolled to one of seven treatment arms (doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin). Dose-limiting toxicities (DLTs) were determined over the first 28 days of treatment, using a 3+3 study design. Results: Of 85 enrolled patients, 81 patients completed the MTD period. The final MTDs for doublet therapy arms (TMZ plus 1 drug) were memantine 20 mg twice a day (BID), mefloquine 250 mg 3 times/week, and metformin 850 mg BID. For triplet therapy arms, the MTDs were memantine 10 mg BID, mefloquine 250 mg 3 times/week, and metformin 850 mg BID. For quadruplet therapy, the MTDs were memantine 10 mg BID, mefloquine 250 mg 3 times/week, and metformin 500 mg BID. DLTs included dizziness related to memantine and gastrointestinal effects related to metformin. Lymphopenia was the most common adverse event (66%); fatigue was the second most common (65%). From study entry, median survival was 21 months; the 2-year survival rate was 43%. Conclusions: Memantine, mefloquine, and metformin can be safely combined with TMZ as treatment for newly diagnosed GBM. The MTDs determined by this study can be used for subsequent clinical trials.