Objective: To evaluate the efficacy of acyclovir in treating infectious mononucleosis (IM) among children of different age groups using propensity score matching (PSM). Methods: This retrospective cohort study included hospitalized children diagnosed with IM at the Children’s Hospital of Nanjing Medical University between January 2018 and December 2023. Patients were categorized into three age groups: infancy and early childhood (<3 years), preschool (4–6 years), and school-age (7–13 years). According to whether acyclovir was administered, patients were divided into an antiviral group and a control group. PSM was performed to balance baseline characteristics. Clinical outcomes, laboratory recovery times, and follow-up data were compared between groups. Results: A total of 733 children were enrolled, with a mean age of 4.78 ± 0.51 years. The most common manifestations included cervical lymphadenopathy (96.0%), fever (86.6%), hepatomegaly (75.6%), splenomegaly (72.6%), pharyngitis (68.9%), and eyelid edema (57.4%). After PSM, 46, 58, and 30 matched pairs were obtained in the three age groups, respectively. In infants and preschool children, the antiviral group showed significantly shorter plasma EBV-DNA clearance time compared with controls (P < 0.05). In preschool children, alanine aminotransferase recovery time was also significantly reduced (P < 0.05). However, acyclovir treatment did not shorten hospitalization duration or symptom resolution time and was associated with longer fever duration in older children. No significant differences were observed in splenomegaly recovery during follow-up. Conclusion: Acyclovir therapy may accelerate viral clearance and promote liver function recovery in younger children with IM, but it does not significantly improve clinical symptoms or overall disease course. Its clinical benefit appears to be age-dependent.