Epilepsy treatment primarily involves antiseizure medications (ASMs) to eliminate seizures and improve the quality of life, but many patients develop drug-resistant epilepsy (DRE), necessitating alternative interventions. This study aimed to evaluate the long-term efficacy and safety of vagus nerve stimulation (VNS) in managing DRE. We retrospectively analyzed data from 105 adult patients treated at Agostino Gemelli Hospital from 1994 to 2022. Among the 73 patients with follow-up data, 80.8% were responders, experiencing significant reductions in seizure frequency over an average follow-up period of 9.4 years. Although 19.2% were non-responders, many of these patients still opted for generator replacements due to improvements in quality of life, such as fewer falls and shorter post-ictal periods. The overall complication rate was 12.3%, with most complications being mild and manageable. These findings suggest that VNS offers substantial long-term benefits for patients with DRE, improving seizure control and quality of life. This study underscores the importance of VNS as a viable long-term treatment option for DRE, highlighting its potential to significantly enhance patient outcomes and quality of life.