Our previous study demonstrated that the maintenance of hippocampal myelination contributes to the development of stress adaptation. Further, we showed that 5-HT_1A receptor in the hippocampus may be involved in the protection of major myelin proteins loss induced by unadaptable excessive stress. However, the mechanism by which activation of 5-HT_1A receptor promote myelination remains unknown. In the present study, we investigated the protective effects of 5-HT_1A receptor agonist flesinoxan on unadaptable stress-induced myelin damage and its molecular mechanisms in mice. Western blot analysis revealed that administration of flesinoxan significantly increased the expression level of BDNF, p-ERK, p-CREB, and Olig2 in the hippocampus of stress-maladaptive mice. Furthermore, in the immunohistochemical analysis, a significant increase in the number of Olig2⁺/BrdU⁺ positive cells were observed in the dentate gyrus of the hippocampus of flesinoxan-treated, but not vehicle-treated, stress-maladaptive mice. The present findings indicate that 5-HT_1A receptor-mediated enhancement of oligogenesis via activation of ERK/CREB/BDNF signaling pathways may be involved in the protection of myelin loss induced by unadaptable excessive stress.