Zika virus (ZIKV) is a global health threat that can cause severe neurological defects, but specific antiviral therapies are lacking. Through a kinase-focused CRISPR-Cas9 screen, we identified cyclin-dependent kinase 2 (CDK2) as an essential host factor for ZIKV infection. We demonstrate that CDK2 directly binds to and phosphorylates the viral RNA polymerase NS5, enhancing its RNA synthesis activity to drive viral replication. In human cells, this phosphorylation also potentiates NS5-mediated degradation of STAT2 and suppression of type I interferon signaling, representing a synergistic immune-evasion mechanism. Pharmacological inhibition of CDK2 with clinical-stage compounds, SNS-032 and Fadraciclib, effectively limited ZIKV replication in human cells, brain organoids, and immunocompromised mice. These inhibitors also restricted Dengue virus replication, indicating that targeting host CDK2 could be a promising strategy against other flaviviruses. Our work unveils CDK2 as a critical host kinase co-opted by ZIKV and establishes its inhibition as a potential host-directed antiviral approach.