© 2022 Elsevier LtdMelittin (MLT) treatment is believed to enhance tumor cell death, apoptotic, and oxidative cytotoxic effects of cisplatin (CSP) via the modulation of Ca2+ channels in several cancer lines. The activation of TRPM2 mediated anticancer and CSP resistance actions via mitochondrial Ca2+ and Zn2+ accumulation-induced mitochondrial reactive free oxygen species (MitSOX) in the glioblastoma cells. The aim was to elucidate the effects of CSP and MLT combination via the TRPM2 stimulation on the tumor cell viability, cell number, cell death (propidium iodide/Hoechst rate), apoptosis, and MitSOX levels in the DBTRG-05MG cells. In the DBTRG-05MG cells, we induced four groups as control, MLT (2.5 μg/ml for 24 h), CSP (25 μM for 24 h), and CSP + MLT. The CSP-induced intracellular Ca2+ influxes to the TRPM2 activation were increased in the cells from coming H2O2 and ADP-Ribose. The influxes were decreased in the cells by the incubations of TRPM2 antagonists (ACA and carvacrol). The incubation of CSP increased the parameters of intracellular Ca2+ responses, mitochondria function, cytosolic free Zn2+ accumulation, apoptosis (caspase −3, −8, and −9), and MitSOX generation in the tumor cells. After the treatment of MLT with/without CSP, the parameters were further increased in the cells. In conclusion, the treatment of MLT increased the anticancer, tumor cell death, apoptotic, and oxidant effects of CSP in the glioblastoma tumor cells via activating the TRPM2. As a result, TRPM2 stimulation by MLT may be utilized as a successful agent in the CSP treatment of glioblastoma tumors.