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Unilateral hemispheric edema may occur with or without seizures. It is a rare entity, found more often in children, than in adults. As many of these patients develop pronounced unilateral complete cortical hemispheric (uni-hemispheric) edema on MRI, we have used the term “cortical unihemispheric brain edema” (CUBE) to describe this entity. We describe a case of CUBE occurring along with a post COVID multi-system inflammatory syndrome in adults (MIS-A). A 30-year-old man was admitted with status epilepticus. He was found to have CUBE and features of MIS-A. He had a history of mild COVID-19 illness one month earlier. He was noted to have persistently elevated inflammatory markers and multiorgan dysfunction compatible with MIS-A. We review the cases of CUBE in the literature and describe the features and etiology of this uncommon syndrome. Furthermore, we discuss the differences between two types of CUBE; cytotoxic CUBE (CUBE-C) and vasogenic CUBE (CUBE-V).