<p>Dysfunction of the autonomic nervous system (ANS) is strongly linked to the pathophysiological mechanisms of depression. Unfortunately, the correlation between depressive-like behaviors and the activation or inhibition of the sympathetic/parasympathetic nervous system has not been systematically explored. This study demonstrated that the pharmacological activation of sympathetic α-/β-adrenergic receptors increased stress susceptibility, whereas their antagonists enhanced stress resistance, thus suggesting a close correlation between sympathetic activity and depressive-like behaviors. Furthermore, arecoline, an agonist of the peripheral parasympathetic muscarinic (M) receptors, has exhibited significant antidepressant effects in multiple murine depression models, and its antidepressant effects could be blocked by the M receptor antagonist known as atropine, thus indicating that parasympathetic excitability regulates depressive-like behaviors. Moreover, arecoline acted on peripheral M receptors to activate glutamatergic neurons in the anterior cingulate cortex (ACC^Glu) via the vagus nerve and nucleus tractus solitarius (NTS) in sequence. Chemogenetic manipulation confirmed that the antidepressant effect of arecoline is dependent on the activation of ACC^Glu neurons, and direct activation of these ACC^Glu neurons exerts an antidepressant effect. Notably, pharmacological activation of peripheral parasympathetic M receptors can regulate the activation of the nodose ganglion (NG)–NTS–ACC^Glu neural axis and modulate depressive-like behaviors. For the first time, this study indicates that peripheral M receptors are promising targets for antidepressants development and proposes a potential antidepressant strategy involving the pharmacological modulation of peripheral autonomic balance.</p>