Aim A total of 30% of individuals with epilepsy are resistant to drug treatment. Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) shows promise for treating drug-resistant epilepsy (DRE), but further research is needed to optimize DBS parameters, including stimulation frequency. This study aimed to reveal the optimal frequency for ANT-DBS by testing the real-time effects of various stimulation frequencies on the ANT among patients undergoing stereoelectroencephalography (SEEG) electrode implantation. Methods Eleven patients (8 males; mean age, 24.2 years; mean epilepsy duration, 13.5 years) were enrolled. Postoperative electrode reconstruction identified ANT contacts for bipolar stimulation between 10 Hz and 100 Hz at 10-Hz increments, with a 1-min interval between stimuli. The effects were analyzed on the basis of spike count, power spectral density, and causal flow. Results Our study revealed that ANT stimulation suppresses seizure focus activity and modulates brain network dynamics, with the effects varying by individual characteristics and frequency. Stimulation at 10-70 Hz reduced spikes (> 50%) and PSD (p < 0.05) in the epileptogenic region while also influencing network connectivity between the epileptogenic zone and adjacent cortical regions, including the frontal, temporal, and insular lobes, as well as the overall brain network. Conclusions Instead of using a fixed high frequency for ANT-DBS, the optimal frequency should be selected for each patient. Patients who do not respond well to high-frequency ANT-DBS can use a lower frequency, such as 10-70 Hz.