Descending necrotizing mediastinitis (DNM) is a life-threatening complication secondary to oropharyngeal abscesses, cervical esophageal perforation, or neck infections spreading along the fascial planes into the mediastinum. Post-thyroidectomy surgical site infection is a highly unusual complication that is typically localized around the incision, but may be propagated into the mediastinum, causing DNM. We encountered a case of this rare complication after thyroidectomy. The patient was a 33-year-old woman who was admitted to our center for left hemithyroidectomy. The surgery was performed without any intraoperative events. However, she later developed fever, hypotension, and tachycardia. Imaging revealed deep neck emphysema and focal pneumomediastinum with infiltration in the anterior neck and mediastinum with abscess formation. Additional imaging at 7 days postoperatively revealed reduced fluid collection deep in the neck with minimal changes in fluid collection in the mediastinum. Esophageal perforation was excluded via an esophagogram, which lead to the conclusion that the infection may have been caused by open thyroidectomy. The patient was treated with prompt medical and surgical intervention. After treatment, she was discharged from the hospital with no further complications. We present our case report as well as a literature review of the diagnosis and treatment of this disease.