Descending necrotizing mediastinitis (DNM) is a rare but serious complication of oral and cervical infections that is associated with high mortality because diagnosis can be difficult or delayed. Early diagnosis and accurate identification of the causative pathogen can significantly reduce mortality, and are critical for the management of these patients. A 56-year-old female was admitted with a sore throat and fever. The initial diagnosis was acute tonsillitis, but she was transferred to the intensive care unit after developing dyspnea. Pleural effusion and mediastinal lesions were detected by computed tomography, and a diagnosis of DNM was confirmed by laboratory tests. Initial treatment consisting of ceftriaxone and vancomycin with chest tube drainage were not effective. Thoracic surgery was performed to completely remove the "moss" tissue, blood clots, and pus. Next-generation sequencing was then performed, and the anti-infective treatment was changed to imipenem and linezolid based on these results. Eventually, the patient's symptoms were controlled, all vital signs were stable, and she was successfully transferred out of the intensive care unit. Next-generation sequencing is a rapid and accurate method for identification of pathogens that can provide a basis for early treatment of DNM, thereby improving patient prognosis and reducing mortality.