Congenital human cytomegalovirus (HCMV) is a significant contributor to liver damage in infants and children. HCMV-encoded IE1 protein plays an important role in viral replication and disease progression. To investigate the effects IE1 on neonate liver, the transgenic mouse model (IE1 mice) and transcriptome sequencing were performed. The results showed that compared to wild-type mice, IE1 can cause liver injury by affecting drug metabolism, fatty acid metabolism, steroid hormone biosynthesis, and retinol metabolism. Furthermore, cytochrome P450 (CYP) enzymes family play a crucial role in liver metabolism disorder of IE1 mice. Combined with the results of the PPI analysis and qRT-PCR validation, Cyp4f39, Cyp3a44, and Cyp3a11 may be the key genes of IE1 causing liver injury. Overall, our study highlights the potential harmful effects of the HCMV IE1 protein on the neonatal liver, offering new insights into the mechanisms underlying liver injury associated with congenital HCMV infection.