Immune thrombocytopenic purpura (ITP) has been described following both coronavirus disease 2019 (COVID-19) infection and COVID-19 vaccination. ITP is a challenging diagnosis of exclusion, and the pathophysiology of these complications is not well understood but believed to be autoimmune in nature. We describe a severe case of ITP following COVID-19 infection in a patient without a history of hematologic or autoimmune disease and his subsequent uneventful course following COVID-19 vaccination. The current Centers for Disease Control and Prevention (CDC) advisory does not identify a history of ITP as a contraindication to COVID-19 vaccination. We compare our study, which describes an uneventful COVID-19 vaccination course with cases that have described recurrences and relapses of ITP following both COVID-19 infection and COVID-19 vaccination. These reports suggest that the placement of some patients into a unique subset among all patients with ITP may be prudent with regard to future COVID-19 vaccination. Through a literature review, we discuss a broader picture of how COVID-19 infection-associated ITP may differ from COVID-19 mRNA vaccination-associated ITP in its demographics, etiology, and outcomes.