Glioblastoma (GB) is an extremely aggressive, highly invasive brain tumor of astrocytic or oligodendrocyte glial origin. This tumor often infiltrates adjacent healthy brain tissue and can migrate significant distances from the primary tumor site. Given the poor overall survival of GB patients and the limited efficacy of current local and systemic treatments, new therapeutic strategies are needed to improve outcomes, reduce side effects, and enhance patients’ quality of life. In recent years, the potential chemotherapeutic effects of natural molecules have been investigated, either as primary agents or in combination with established chemotherapies in various types of cancer. Melatonin (MLT, N-acetyl-5-methoxytryptamine) is an endogenous indolamine primarily secreted by the pineal gland. MLT appears to discriminate between normal and tumoral cellular contexts and to modulate appropriate actions, thereby acting as a “smart killer” against cancer cells; however, further studies are needed to clarify this apparently paradoxical behavior. This review aims to summarize recent findings on the potential regulatory role of MLT in the modulation of key intracellular pathways in GB, underlining its potential role as a complementary adjuvant to conventional therapies. The clinical advantage of MLT in GB patients has not been demonstrated in randomized controlled trials; therefore, multicenter studies with well-defined objectives, appropriate dosage schedules, and clear patient classification are needed.