Major depression disorder (MDD) is one of the most common psychiatric disorders and one of the leading causes of disability in worldwide. Both inflammation and GABAergic dysfunction have been implicated in the pathophysiology of MDD. Caspase-1, a classic inflammatory caspase, regulates AMPARs-mediated glutamatergic neurotransmission. However, the role of caspase-1 in chronic stress-induced GABAergic dysfunction remains largely unknown. In this study, we found that serum and hippocampal caspase-1-IL-1β levels increased significantly in chronic restraint stress (CRS) mice, and a significant negative correlation occurred between levels of caspase-1 and depression-like behaviors. Furthermore, CRS significantly decreased GAD67 mRNA levels and GABAergic neurotransmission accompanied by the reduction of GABA concentration, reduced the amplitude and frequency of mIPSCs inhibitory postsynaptic currents (mIPSCs) and the decreased surface expression of GABAARs γ2 subunit in the hippocampus. Genetic deficiency of caspase-1 not only blocked CRS-induced depression-like behaviors, but also alleviated CRS-induced impairments in GABAergic neurotransmission. Finally, reexpression of caspase-1 in the hippocampus of Caspase-1−/−mice increased susceptibility to stress-induced anxiety- and depression-like behaviors through inhibiting GAD67 expression and GABAARs-mediated synaptic transmission. Our study suggests that CRS dysregulates GABAergic neurotransmission via increasing the levels of caspase-1-mediated neuroinflammation in the hippocampus, ultimately leading to depression-like behaviors. This work illustrates that targeting caspase-1 may provide potential therapeutic benefits to stress-related GABAergic dysfunction in the pathogenesis of MDD.