Neonatal appendicitis is a rare disease with a high mortality rate. Appendicitis is difficult to diagnose in neonatal and infant populations because it mimics other more common conditions in these age groups. Furthermore, signs and symptoms of appendicitis are often nonspecific in nonverbal patients and a high index of suspicion is necessary to initiate the appropriate diagnostic work-up. The keys to successful management of appendicitis in infants include keeping the diagnosis on the differential in the setting of unexplained intra-abdominal sepsis, following a diagnostic algorithm in the work-up of infant abdominal pathology, and performing appendectomy once the diagnosis is confirmed.