BACKGROUND Cytotoxic lesions of the corpus callosum (CLOCC) is a rare clinical and radiological syndrome that has been associated with various infectious etiologies. CLOCC are among the recently described neurological associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with coronavirus disease 2019 (COVID-19). We report a case of CLOCC in a man with SARS-CoV-2 infection who presented with auditory hallucinations and rapidly developed systemic inflammatory response syndrome (SIRS). CASE REPORT A 23-year-old man with no past medical and psychiatric history presented with auditory hallucinations, restlessness, and suicidal ideations. A nasopharyngeal swab specimen tested using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was positive for SARS-CoV-2. A brain MRI revealed an isolated oval-shaped lesion in the splenium of the corpus callosum, with hyperintense signal on diffusion-weighted imaging (DWI) and hypointense on apparent diffusion coefficient (ADC) maps, suggestive of CLOCC. After a dramatic hospital course associated with multiple organ dysfunction syndrome (MODS) and severe intra-abdominal and cerebral bleeding, he developed cardiac arrest and died on hospital day 15. CONCLUSIONS This case highlights the need for increased vigilance for the atypical manifestations of SARS-CoV-2 infection. In addition, it suggests that CLOCC can be considered as a differential diagnosis by clinicians in patients with SARS-CoV-2 infection who present with unexplained neurological and neuropsychiatric symptoms, leading to poor outcome.