Major depressive disorder (MDD) is a common psychiatric disorder worldwide; however, the cure rate remains low. Therefore, it is necessary to develop additional safe and effective antidepressants. Accumulating evidence show that PACAP (pituitary adenylate cyclase-activating polypeptide) and its receptor PAC1 have been implicated in the pathogenesis of stress related disorders, such as MDD. However, PACAP and its peptide antagonist are subject to rapid degradation, and therefore, not suitable for the treatment. Here, we developed novel small-molecule, non-peptide, and high-affinity PAC1 antagonists. In this study, we aimed to characterize the PAC1 antagonism as a new therapeutic option for MDD treatment, performing behavioral pharmacological experiments in mice. A single dose of the PAC1 antagonist displayed a fast and lasting antidepressant-like effects in repeated social defeated stress mice. Interestingly, this effect lasted over 8 weeks. The PAC1 antagonist did not exhibit behavioral impairments, including pre-pulse inhibition deficits and cognitive deficits in naive control mice. These results suggest that our novel PAC1 antagonist has the potential to be a robust antidepressant with a high safety profile.