The role of definitive radiotherapy (dRT) and debulking surgery (DS) for patients with locally advanced, unresectable, Masaoka-Koga stage III thymomas was not well studied. Unresectable tumor refers to tumor that could not be completely resected because of invasion of surrounding organs. Consecutive patients with unresectable stage III thymomas between 2000 and 2017 were reviewed. According to the treatment intent and radiation dose, patients were categorized into a dRT group and a non-dRT group. The former group included patients who received radiotherapy at doses ≥ 54 Gy after DS or biopsy. The latter group included patients who did not receive radiotherapy and those who received a radiation dose < 54 Gy. A total of 82 patients were included. Compared with non-dRT, dRT significantly improved 5-year overall survival (OS, P = 0.003), progression-free survival (PFS, P = 0.008), and freedom from locoregional failure (FFLF, P < 0.001). Compared with biopsy alone, DS did not improve OS, PFS, FFLF. On multivariate analysis, dRT was an independent prognostic factor for OS (hazard ratio [HR]: 2.37, P = 0.024), PFS (HR: 2.40, P = 0.004), and FFLF (HR: 3.83, P = 0.001). In conclusion, dRT was an effective and beneficial treatment for patients with unresectable Masaoka-Koga stage III thymoma.