Neuroblastoma is a solid malignant tumor of the sympathetic nervous system, which accounts for 8-10% of childhood cancers. Considering the overall high risk and poor prognosis associated with neuroblastoma, effective therapeutics should be developed to improve patient survival and quality of life. A recent study showed that a proteasome inhibitor, carfilzomib (CFZ), reduced cell viability of SK-N-BE(2)-M17 neuroblastoma cells. Therefore, we investigated the molecular mechanisms by which CFZ lower the cell viability of neuroblastoma cells. CFZ reduced cell viability via cell cycle arrest at G2/M and apoptosis, which involved caspase activation (caspases-8, 9, 4, and 3), endoplasmic reticulum stress, reactive oxygen species production, mitochondrial membrane potential loss, and autophagy in a dose- and time-dependent manner. The effect of CFZ was additive to that of cisplatin (Cis), a well-known chemotherapeutic drug, in terms of cell viability reduction, cell cycle arrest, and apoptosis. Importantly, the additive effect of CFZ was maintained in Cis-resistant neuroblastoma cells. These results suggest that CFZ can be used in combination therapy for patients with neuroblastoma to overcome the resistance and adverse side effects of Cis.