Epstein-Barr Virus (EBV) is estimated to infect greater than 98% of adults worldwide and is one of the most common human viruses. EBV infection can lead to acute infectious mononucleosis characterized by fever, fatigue, malaise, sore throat, and lymphadenopathy. Elevated liver function tests (LFTs) and hepatosplenomegaly may also be present. This infection usually lasts over a period of weeks or months and is self-limited. Infected individuals, however, may suffer rare complications. Acute acalculous cholecystitis (AAC) is an atypical complication of infectious mononucleosis. The case of a young healthy adolescent female with primary EBV infection complicated by AAC is reported. Providers should be aware that many pediatric and adult cases of AAC due to EBV resolve with conservative treatment. Surgical intervention has not been described as necessary or indicated in the context of AAC caused by EBV and should only be considered in severe cases that are not responding to conservative therapy.