Temozolomide (TMZ) is an oral alkylating agent that is considered the standard therapy in primary intracranial malignancies. The medication is well tolerated with a most common side effect of bone marrow suppression that is encountered in a small proportion of patients, often reversible with medication discontinuation and supportive treatment. Rarely, aplastic anemia can develop during treatment with TMZ. Here, we present a case of a patient who developed aplastic anemia following treatment with TMZ. We offer a review of the existing literature to have a better understanding of the causative effect and to examine the characteristics and outcomes when aplastic anemia develops during treatment with TMZ.