Malignant gliomas constitute one of the deadly brain tumors with high degeneration rate. Though temozolomide (TMZ) is the first-line drug for glioma, its efficacy has decreased due to chemo-resistance. Repurposing synthetic and natural compounds have gained increasing interest in glioma. Hence, we combined chloroquine (CHL) a synthetic drug, naringenin (NAR) and phloroglucinol (PGL) (natural derivatives), to investigate whether the apoptotic effect of these drugs both alone and in combination, enhances the anti-tumor effects of TMZ in an in vitro and in vivo orthotopic xenograft glioma model.