Malignant pleural mesothelioma is a rare but aggressive cancer with limited treatment options. Percutaneous cryoablation is emerging as a promising treatment option for control of local recurrence and for palliative management of the disease-related symptoms. At times, recurrent malignant pleural mesothelioma is difficult to target as it can recur within the mediastinum and can be surrounded by vital organs and large vessels. This case report describes a challenging yet safe and successful transvertebral approach for percutaneous cryoablation of a paraesophageal mass for palliative treatment of a patient with single-site recurrent metastatic malignant pleural mesothelioma within the mediastinum.