〔Abstract〕 Objective To compare the efficacy and safety of different doses of ganciclovir in the treatment of congenital cytomegalovirus infection in newborns. Methods Fifty newborns with congenital cytomegalovirus infection admitted to the Third Affiliated Hospital of Zhengzhou University from February 2019 to February 2022 were selected. According to different doses of ganciclovir, they were divided into a low-dose group (6.0 mg·kg^-1) and a high-dose group (7.5 mg·kg^-1), with 25 cases in each group. Clinical symptom scores, liver function, virological examination results, clinical efficacy, and incidence of side effects were compared between the two groups. Results After treatment, the scores of fever, vomiting, diarrhea, jaundice, hepatomegaly, and abnormal primitive reflex of the two groups of children were lower than before treatment. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), human cytomegalovirus deoxyribonucleic acid (CMV-DNA), copy number variant immunoglobulin G (CNV-IgG), and copy number variant immunoglobulin M (CNV-IgM) were lower than those before treatment, and the differences were statistically significant (P < 0.05). However, there was no statistically significant difference between the two groups (P > 0.05); The incidence of side effects in the low-dose group was lower than that in the high-dose group, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in the total effective rate between the two groups (P > 0.05). Conclusion The therapeutic effects of high-dose and low-dose ganciclovir in the treatment of congenital cytomegalovirus infection in newborns are comparable, but the safety of low-dose is higher.