Objective: To evaluate the efficacy of acyclovir in treating infectious mononucleosis (IM) among children of different age groups using propensity score matching (PSM) method. 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 according to the age: the infancy and early childhood group(<3 years), preschool group(4-6 years), and school-age group(7-13 years). According to whether acyclovir was administered, patients were divided into an antiviral group and a control group. After balancing baseline confounding factors by the PSM method, the differences in prognostic indicators between the two groups were compared. Results: A total of 733 children with IM were enrolled, with a mean age of(4.78 ± 0.51)years old. 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%). Before PSM, there were statistically significant differences in fever, pharyngitis, hepatosplenomegaly, white blood cell count, proportion of atypical lymphocytes, CD4⁺/CD8⁺ ratio and plasma EBV-DNA load among children of different age groups(all P < 0.05). After PSM, 46 pairs in the infancy and early childhood group, 58 pairs in the preschool group and 30 pairs in the school-age group were successfully matched(all P > 0.05). Compared with the control group, the antiviral group in the infant infancy and early childhood group had longer time required for the resolution of pharyngitis, the reduction of white blood cell count to <10×10⁹/L, but shorter time required for the decrease of plasma EBV-DNA load to < 500 copies/mL(all P < 0.05); the antiviral group in the preschool group had longer time required for temperature recovery and pharyngitis resolution, but shorter time required for the reduction of serum alanine transaminase(ALT)to < 40 U/L and plasma EBV-DNA load to < 500 copies/mL(all P < 0.05); the antiviral group in the school-age group had longer hospital stay and time required for temperature recovery(all P < 0.05). At 30 days after treatment, there was no statistically significant difference in the recovery of splenomegaly among all age groups between the two groups. Conclusion: Acyclovir therapy may accelerate viral clearance and promote liver function recovery in infants and preschool children with IM, but it does not significantly improve clinical symptoms or overall disease course. Its clinical benefit appears to be age-dependent.