Background The treatment of recurrent mediastinal lymph node metastasis (MLNMs) is challenging. We conducted this study to evaluate the effectiveness and safety of computed tomography (CT)‐guided percutaneous iodine‐125 brachytherapy for MLNMs. Methods We retrospectively analyzed 33 patients with recurrent MLNMs treated with CT‐guided interstitial implantation of iodine‐125 seeds. Regular contrast‐enhanced CT was conducted to evaluate the tumor response. Follow‐up survival, quality of life, and adverse events were analyzed. Results The number of implanted seeds was 16–85 (median, 40). The matched peripheral dose was 110–160 Gy. The patients were followed up for 5–24 months (median, 14 months). At the last follow‐up or death, complete response to therapy was achieved in 11 patients (33.3%) and partial response in 18 patients (54.5%). The median survival time of this cohort was 15.2 months (95% confidence interval [CI], 9.9–20.5 months); the estimated one‐ and two‐year survival rates were 68.6% and 31.1%, respectively. The Karnofsky performance score increased significantly after the procedure (p = 0.007). Pneumothorax with pulmonary compression of 30% to 40% occurred in five (15.2%) patients and was cured after drainage. No severe complications occurred. Conclusions CT‐guided iodine‐125 brachytherapy provided a safe and effective choice for recurrent mediastinal lymph node metastasis with significant local therapeutic effects and minor complications, especially for patients who were not eligible for surgical resection and had failed to benefit from systemic therapy.