Background <p>Epstein-Barr virus (EBV) frequently causes temporary liver injury during initial infection, and in severe cases, fulminant hepatitis and liver failure can occur. This study aimed to examine the expression of key Absent in Melanoma 2 (AIM2)-pathway pyroptosis mediators (AIM2, Caspase-1, Gasdermin D[GSDMD], IL-1β, and IL-18) in the blood of children experiencing primary EBV infection and to assess their correlation with viral load and liver injury.</p> Methods <p>Sixty-five children hospitalized with primary EBV infection were enrolled and categorized based on liver function (Abnormal Liver Function, <i>n</i> = 35; Normal Liver Function, <i>n</i> = 30). Control groups included 30 healthy children with past EBV infection and 30 healthy seronegative children. Real-time reverse transcription polymerase chain reaction was used to detect the mRNA expression levels of AIM2, Caspase-1, and GSDMD. IL-1β and IL-18 serum concentrations were measured by enzyme-linked immunosorbent assay. The institutional clinical laboratory was responsible for routine biochemical indicators, including EBV-DNA load.</p> Results <p>The study indicated that children with primary EBV infection exhibited significantly elevated mRNA expression of AIM2, Caspase-1, and GSDMD, alongside increased serum IL-1β and IL-18 concentrations, compared to both control groups. Within the primary infection group, serum EBV-DNA load showed positive correlations with these pyroptosis markers. Furthermore, patients with primary EBV infection and abnormal liver function had significantly higher levels of these mediators than infected patients with normal liver function. AIM2 mRNA expression also positively correlated with Caspase-1 mRNA, GSDMD mRNA, IL-1β, and IL-18 levels.</p> Conclusions <p>AIM2-dependent pyroptosis is implicated in the systemic inflammatory response to EBV and may contribute to the immunopathogenesis of EBV-associated hepatitis.</p>