Tetanus is an infection caused by a neurotoxin produced by a bacterium called Clostridium tetani. One of tetanus management is to use therapeutic plasma exchange (TPE) facilities as a therapeutic modality, which is rarely available in most severe tetanus populations. TPE is therapeutic apheresis that is applied either as primary or secondary therapy in various kinds of diseases. We reported a case of a 60-year-old man diagnosed with observed general onset tonic-clonic seizure with trismus due to tetanus. The patient came with a chief complaint of mouth stiffness with difficulty opening his mouth (mouth opening of 5 cm). His condition was followed by generalized spasms, especially when triggered by loud noises and light. The patient had a 2-week history of tooth pain due to dental caries with no response to pain relievers. The patient then received TPE on the eighth day of treatment, two times with 3000 ml plasma exchange, 2500 ml albumin 5%, and 500 ml NaCl 0.9%. Based on clinical evidence, TPE effectively eliminates toxins released by Clostridium tetani in tetanus patients. Removing circulating autoantibodies, immune complexes, cytokines, and other inflammatory mediators is fundamental to this process. Cytokines are one of the molecules that potentially cause damage but can be removed through TPE. Significant clinical outcomes were shown after the patient received TPE. TPE can maintain hemodynamic stability and faster extubation time and reduce trismus, muscle spasms, and seizure frequency until they no longer appear.