A diagnosis of multisystem inflammatory syndrome in children should be made in the appropriate context and after ruling out other infectious causes. At the same time, clinicians should be diligent as the initial presentation can be unusual and the clinical picture can evolve over time. We report a case that was initially diagnosed as a retropharyngeal infection that did not improve on appropriate antimicrobial coverage. However, as the clinical picture evolved, the patient was found to have multisystem inflammatory syndrome in children and appropriately responded to immunomodulatory treatment. Pediatric infectious diseases practice has been significantly affected by the COVID-19 virus and multisystem inflammatory syndrome in children; data are still emerging as the pandemic evolves. We report this case and conduct literature review to expand the body of evidence about the association between multisystem inflammatory syndrome in children and retropharyngeal involvement.