Neuroleptic malignant syndrome (NMS) is a rare but serious and sometimes fatal complication in patients taking antipsychotic drugs, and its underlying mechanism still remains unclear. The pharmacotherapy for psychotic disorders is complicated and often involves a combination of two or more drugs, including drugs other than antipsychotics. We used the Japanese Adverse Drug Event Report (JADER) database to broadly investigate the drugs associated with NMS, following their related pathways, as well as the drug-drug interactions (DDIs) in NMS. Single-drug signals were evaluated using the reporting odds ratio and proportional reporting ratio, and drug pathways were investigated using the Kyoto Encyclopedia of Genes and Genomes. DDIs were evaluated using the Ω shrinkage measure and Chi-square statistics models. All drugs associated with 20 or more NMS cases in the JADER database exhibited signals for NMS. Pathways associated with the drugs included the dopaminergic or serotonergic synapses. DDIs leading to NMS were confirmed for several drug combinations exhibiting single-drug signals. Although this study confirmed the significant association of various drugs, including non-psychotics, with NMS and suggested that various pathways related to these drugs may be involved in the progression of NMS, further investigation is needed to elucidate the pharmacological mechanisms.