Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes, including Ctnnd2 as a candidate gene. Ctnnd2 knockout mice, serving as an animal model of autism, have been demonstrated to exhibit decreased density of dendritic spines. The role of melatonin, as a neurohormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines, in Ctnnd2 deletion-induced nerve injury remains unclear. In the present study, we discovered that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits, spine loss, impaired inhibitory neurons, and suppressed phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signal pathway in the prefrontal cortex. Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice. Furthermore, the administration of melatonin in the prefrontal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region. The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor, wortmannin, and melatonin receptor antagonists, luzindole and 4-phenyl-2-propionamidotetralin, prevented the melatonin-induced enhancement of GABAergic synaptic function. These findings suggest that melatonin treatment can ameliorate GABAergic synaptic function by activating the PI3K/Akt signal pathway, which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.