Objective To explore the molecular mechanism of sesame oil in treating insomnia by network pharmacology, bioinformatics, and molecular docking methods.Methods Sesame oil targets are screened by TCMSP and Herb databases, while insomnia-related targets are searched in GeneCard, ETCM, DrugBank database, and GSE189993 data set. Then, the intersection is found to obtain the common targets. The protein interaction network is constructed by the String software for gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The binding abilities of the active ingredients and the targets are evaluated by molecular docking on the AutoDock tool.Results A total of 160 common targets are screened, while 8 key genes are identified by topological analysis. These targets are related to nervous system-related pathways, including neuroactive ligand-receptor interaction, serotonergic synapses, and dopaminergic synapses. The results of molecular docking show that the corresponding proteins of 7 key genes (TNF, IL6, IL1B,etc.) have strong binding activity with the active component of sesame.Conclusion Sesame oil plays a therapeutic role in insomnia through multi-component, multi-target, and multi-pathway synergy.