Splenic infarction is a rare and likely underdiagnosed complication of Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). Here, we describe an 18-year-old Guyanese male with persistent severe left-sided abdominal pain found to be EBV positive and have a large splenic infarct, along with a transient decrease in protein C, protein S, and antithrombin III activity levels. He was treated with supportive care and anticoagulated with heparin and apixaban. We review prior reports and perspectives on underlying pathophysiology, diagnosis, and the management of these cases, which likely do not require anticoagulation but may be considered on a per-case basis.