Objective. To investigate the efficacy differences between acyclovir and ganciclovir in the treatment of children with Epstein–Barr virus (EBV)- associated infectious mononucleosis (IM). Methods. A total of 128 children with EBV-IM who were admitted to our hospital from February 2019 to February 2021 were selected and randomly divided into the acyclovir group (n = 64) and the ganciclovir group (n = 64) according to the random number table method. All the children were given symptomatic treatments such as protecting the liver and reducing fever. On this basis, the acyclovir group was given an intravenous drip of acyclovir, while the ganciclovir group was given an intravenous drip of ganciclovir. The treatment was continued for 7 days. After the treatment, the clinical efficacy, disappearance time of symptoms and signs, related blood routine indexes, EBV-DNA negative conversion rate, and the incidence of adverse reactions during the treatment were compared between the two groups. Results. After treatment, the total effective rate of the ganciclovir group (92.19%) was higher than that of the acyclovir group (73.44%) and the difference was statistically significant P < 0.05 . The disappearance time for the symptoms and signs of angina, fever, lymphadenopathy, hepatomegaly, and splenomegaly in the ganciclovir group was lower than that in the acyclovir group, and the difference was statistically significant P < 0.05 . After treatment, the levels of atypical lymphocyte proportion, lymphocyte proportion, and WBC count in the two groups were lower than those before treatment, the levels in the ganciclovir group were lower than those in the acyclovir group, and the difference was statistically significant P < 0.05 . After treatment, the EBV-DNA negative conversion rate (81.25%) in the ganciclovir group was higher than that in the acyclovir group (60.93%) and the difference was statistically significant P < 0.05 . During treatment, the incidence of adverse reactions in the ganciclovir group was significantly lower than that in the acyclovir group and the difference was statistically significant P < 0.05 . Conclusion. In the treatment of children with EBV-IM, the therapeutic effect of ganciclovir is obviously superior to that of acyclovir. Ganciclovir can quickly eliminate the symptoms of angina, fever, enlarged lymph nodes, and other signs in children, can improve abnormal blood indicators, and has a higher negative conversion rate of EBV and less adverse reactions.