Objective Ventricular arrhythmias originating from the upper ventricular septum have been described, but the involvement of the His-Purkinje System (HPS) remains underexplored. This study aims to characterize ventricular arrhythmias arising from the upper ventricular septum with HPS involvement and assess the role of catheter ablation in this patient population. Methods We retrospectively analyzed cases of VT ablation performed at Taipei Veterans General Hospital between 2018 and 2024. The study included patients with structural heart disease presenting with clinical polymorphic VT or VF and diseased HPS. Results Nine patients (78% male) with VT involving the HPS region were analyzed. The mean LVEF was 45.3 ± 10.5%, and the LVIDD was 53.5 ± 10.2 mm. Structural heart disease was ischemic in 5 patients (55%), dilated non-ischemic cardiomyopathy in 3 (33%), and valvular cardiomyopathy in 1 (11%). All patients had documented VF or unstable VT on ECG or device recordings. VT was inducible in all cases, with an average of 2.67 ± 1.15 VT morphologies per patient. Strategic Multielectrode Positioning (StaMP) mapping, late ventricular activation (LAVA) modification, and pace mapping for stable morphologies were applied. All arrhythmogenic areas were adjacent to diseased HPS. These strategies achieved non-inducibility of VT/VF in all patients. Post-ablation, conduction system injury occurred in all patients, manifesting as prolonged QRS duration or pacing dependency. One patient experienced recurrence, successfully managed with a repeat procedure. Conclusion Catheter ablation is a feasible treatment for unstable VT and VF in patients with structural heart disease. Achieving non-inducibility often necessitates ablation of the LV septum and opposing RV septum, albeit at the risk of conduction system injury and pacing dependency. These findings provide insights into ablation strategies for managing this complex patient population.