Growing evidence demonstrates that the delta opioid receptor (DOP) is an attractive candidate for novel antidepressants with the potential to exhibit rapid action with few adverse effects. However, the underlying detailed functional mechanism remains elusive. We previously reported that the selective DOP agonist, KNT-127, produced robust antidepressant-like effects in the forced swimming test (FST) in mice. Thus, we attempted to identify the cellular mechanism underlying this effect. As a result, the selective mTOR inhibitor, rapamycin, and the PI3K inhibitor, LY294002, blocked the antidepressant-like effects of KNT-127 in the FST. KNT-127 promoted the phosphorylation of mTOR signal-related proteins, Akt and p70S6K, in the medial prefrontal cortex in the protein immunoblotting assay. The bilateral microinfusion of KNT-127 into the infralimbic cortex (IL-PFC) reduced immobility in the FST. Furthermore, whole-cell voltage-clamp recordings revealed that the frequency of mEPSCs in the IL-PFC increased and that of mIPSCs decreased with the bath application of KNT-127, which was blocked by pretreatment with rapamycin. Taken together, our results suggest that KNT-127 directly activates neuronal excitability in the mouse IL-PFC through PI3K-Akt-mTOR-p70S6K signaling pathway to exert antidepressant-like actions. These results could indicate the first steps in elucidating the complete mechanical functions of DOPs as a potential candidate target for novel antidepressants.