Cytotoxic lesions of the corpus callosum (CLOCCs) are secondary lesions associated with a variety of clinical causes. The presence of a small and reversible lesion in the splenium of corpus callosum with restricted diffusion on cranial magnetic resonance imaging is the defining feature. The clinical-radiological manifestations have been documented as mild and reversible. Severer presentations were scarcely reported. In this report, we described a 25-year-old man with preceding fever, worsening somnolence, and convulsions. He was diagnosed with acute meningoencephalitis and Mycoplasma pneumoniae infection after workups. After medical treatments, he had neurological deterioration and progressing CLOCCs from a small oval lesion in the center of splenium extending to the whole corpus callosum and bilaterally adjacent white matter. The patient received intravenous methylprednisolone and immunoglobulin successively, and his neurological conditions improved. The CLOCCs, not always mild and reversible, could present with severe clinicoradiological features.