COVID-19 infections have a broad spectrum of severity, with more severe symptoms observed in elderly patients, patients with underlying comorbidities, and patients with unvaccinated status. This case series aims to highlight two cases of unvaccinated patients who developed COVID-19 encephalopathy, contrasted with a vaccinated patient with similar risk factors. This article highlights the unique characteristics of COVID-19 encephalopathy to guide clinicians while approaching the broad diagnosis of acute encephalopathy or altered mental state in hospitalized patients. Current literature was reviewed and summarized the information available regarding encephalopathy separate from the more complex encephalitis and encephalomyelitis.