Multisystem inflammatory syndrome in children is a recently described complication in the late phase of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection involving systemic hyperinflammation and multiorgan dysfunction. The extent of its clinical picture is actively evolving and has yet to be fully elucidated. While neurologic manifestations of SARS-CoV-2 are well-described in the adult population, reports of neurologic complications in pediatric patients with SARS-CoV-2 infection are limited. We present a pediatric patient with SARS-CoV-2 infection with development of multisystem inflammatory syndrome and acute encephalopathy causing delirium who was found to have a cytotoxic lesion of the corpus callosum on neuroimaging. Cytotoxic lesions of the corpus callosum are a well-known, typically reversible entity that can occur in a wide range of conditions, including infection, seizure, toxins, nutritional deficiencies, and Kawasaki disease. We hypothesized that the cytotoxic lesion of the corpus callosum, in the index case, was secondary to the systemic inflammation from SARS-CoV-2 infection, resulting in multisystem inflammatory syndrome in children.