Impaired differentiation of newborn neurons or abnormalities at the synapses resulted from stress maladaptation could be the key etiology of depression. Recent studies have shown that mTOR, a crucial factor for neuronal differentiation and synapse development, acts as a common factor that mediates the rapid antidepression effects of several new-class antidepressants. In this study, the antidepressant-like activity of securinine, an alkaloid that has central nervous system stimulation ability, was investigated. Both securinine and its enantiomer virosecurinine exhibited potent in vitro activity on neuronal differentiation and synapse development in Neuro-2a cells and cultured hippocampal neurons, and this activity was dependent on the activation of the AKT-mTOR-S6K pathway. Interestingly, only securinine but not virosecurinine showed mTOR stimulation and antidepressant-like activity in mice. Importantly, a single dose of securinine was capable of alleviating the behavioral deficits induced by both acute and chronic stress models within 30 min of administration, suggesting that securinine has rapid onset of action. Moreover, neither a single dose nor a 3 week treatment of securinine had adverse effects on exploratory locomotion of mice. Together, this study identifies that securinine is a potent agent in promoting neuronal differentiation and synapse formation and shows rapid antidepressant-like activity, without inducing abnormal locomotion, via mTOR activation.