A link between amoxicillin-induced rash in infectious mononucleosis and allergy has been previously reported. However, the pathophysiological cause and aspects are unclear. Additionally, the complex immunological interaction between the host and Epstein-Barr virus needs to be studied. This article reports a case of amoxicillin-induced rash in infectious mononucleosis resulting in an exuberant rash, facial edema, and marked eosinophilia, which prompted additional workup. Both the eosinophilia and the rash brought to light a possible association with a persistent delayed-type hypersensitivity. Further scientific discussion and investigation can identify predictive indicators that can portend clinical outcome.