This study aims to investigate the neuromodulatory effects of interictal short-term high-frequency stimulation on both the epileptogenic zone (EZ) and distributed networks, thereby advancing our understanding of the mechanisms underlying the therapeutic efficacy of chronic subthreshold cortical stimulation in refractory epilepsy. Eight patients with epilepsy undergoing stereoelectroencephalography monitoring during pre-surgical evaluation, with periodic spikes observed during the interictal period, were included. Short-term high-frequency stimulation (STHFS) and incremental current stimulation protocols were applied to the EZ. Spike rate, amplitude and spectral power were quantitatively assessed during the interictal (baseline), stimulation and post-stimulation periods. Functional network connectivity was evaluated using the directed transfer function and partial directed coherence. During STHFS, the spike rate, amplitude and spectral power decreased significantly compared with the baseline period. In the post-stimulation period, the spike rate, amplitude and spectral power rapidly rebounded and fluctuated around the baseline. Incremental current stimulation resulted in a gradual reduction in spike rate and spectral power, with maximal inhibition achieved at a specific current intensity. Functional connectivity exhibited individualized patterns across frequency bands during STHFS. In individual patients, specific brain regions consistently demonstrated reduced functional connectivity throughout the stimulation process. Short-term high-frequency stimulation effectively inhibits neuronal excitability in the EZ, with the degree of inhibition dependent on stimulation intensity. STHFS has an anti-epileptic effect in the local EZ region and stably regulates the distributed network. Yan et al. reported that short-term high-frequency electrical stimulation of the epileptogenic zone during the interictal period consistently suppressed spike rate, amplitude and spectral power. Additionally, the regulatory effect of this stimulation extends beyond the local epileptogenic zone and modulates distributed brain networks in individual patients.