De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders, leading to haploinsufficiency, cortical hyperexcitability, epilepsy, and motor impairments. STXBP1 encodes for Munc18-1, an essential protein for synaptic transmission. In a mouse model of the disease, we found that excitatory synapses, not inhibitory synapses, are impaired during early stages of the disease. Consequently, excitatory synapses fail to recruit parvalbumin-positive (PV) inhibitory interneurons in feedforward inhibitory microcircuits, leading to cortical hyperexcitability. In this study, we tested the potential therapeutic efficacy of positive allosteric modulators targeting AMPA receptors, known as ampakines, in rescuing the phenotypic abnormalities observed in Stxbp1hap animals. Employing a brain slice preparation, we found that ampakines effectively restored the recruitment of PV cells in response to synaptic stimulation, as assessed by electrophysiology and calcium imaging. Furthermore, ampakines prevented the hyperexcitability of pyramidal neurons induced by prolonged synaptic stimulation. Next, the impact of ampakines was assessed in vivo, focusing on spontaneously occurring spike-wave discharges (SWDs) in the cortex (the equivalent of seizures in patients). Intraperitoneal injection of ampakines resulted in a significant reduction in the frequency of SWDs, that lasted for a duration in the range of the compound half-life. These findings underscore the potential of ampakines as a promising therapeutic intervention for addressing the pathophysiological manifestations associated with STXBP1 encephalopathy.