Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin-associated protein-like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus-mediated knock-down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus-mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg2+-free epilepsy cell model. Down-regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma-aminobutyric acid A receptor β2/3 (GABAARβ2/3) membrane protein, without affecting total GABAARβ2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABAARβ2/3 and gamma-aminobutyric acid receptor-associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABAAR function, and may be a promising target for the development of epilepsy treatment.