To assess the safety and efficacy of treatment for intraductal papillary mucinous neoplasm (IPMN) involving the main pancreatic duct (MPD) using endoscopic retrograde cholangiopancreatography (ERCP) combined with digital single-operator pancreatoscopy and radiofrequency ablation (RFA). A retrospective analysis was performed. Patients with episodes of acute pancreatitis at the First Affiliated Hospital of Chongqing Medical University were screened. When the diagnosis of IPMN was confirmed by ERCP with pancreatoscopy, patients who underwent endoluminal RFA treatment were enrolled. The most frequent complications were monitored to assess the safety of treatment. Disease progression and recurrence of pancreatitis symptoms were regarded as the indicators of treatment efficacy. In total, 50 patients were screened, and 14 patients who undertook the lesion ablation using RFA were enrolled. Mild adverse events occurred, while they were relieved under symptomatic treatment. No severe complications were recorded. All patients received regular follow-ups, during which an episode of IPMN-related pancreatitis occurred in 1 patient, and disease progression was found in 1 patient who successively underwent pancreaticoduodenectomy. Regional treatment of IPMN lesions in the MPD exhibited satisfactory effect in preventing lesion progression and relieving pancreatitis symptoms through the combined use of ERCP with pancreatoscopy and RFA, without causing severe complications.