In this report, we describe the case of a 17-year-old boy with progressive respiratory failure requiring extracorporeal support who met clinical criteria for a presumptive diagnosis of electronic cigarette or vaping-associated acute lung injury (EVALI), with clinical, pathologic, and laboratory evidence of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). The patient in our report had a history of tetrahydrocannabinol and nicotine electronic cigarette use for months leading up to his presentation of fever, headache, emesis, and weight loss with respiratory distress. Multiple potential diagnoses were explored, and the patient's respiratory status improved, and he was initially discharged from the hospital. Roughly one week later, the patient was readmitted for worsening respiratory distress. The patient then met sufficient criteria for a potential diagnosis of HLH and MAS (elevated ferritin level, inflammatory markers, and cytopenia) to warrant a bone marrow aspirate, which revealed rare hemophagocytic cells. Given the severity of his symptoms and laboratory evidence of HLH and MAS, the patient was started on a course of steroids and anakinra. Although laboratory markers improved after treatment, the patient's respiratory failure worsened, ultimately progressing to a need for mechanical ventilation and extracorporeal support and leading to worsening multiorgan system failure and, ultimately, death. To the best of our knowledge, this is the first report of a patient with a presumptive diagnosis of EVALI with evidence of HLH and MAS, raising the possibility that macrophage activation may play a role in the pathogenesis of EVALI.