Most of the antiviral drugs in the market are designed to target viral proteins directly. They are generally considered safe for human use. However, they also suffer from several inherent limitations, in particular, narrow-spectrum antiviral profiles and liability to drug resistance. The other strategy for antiviral drug development is targeting host factors, which are highly involved at different stages in the viral life cycle. In contrast to direct-acting antiviral agents, host-targeting antiviral ones normally exhibit broad-spectrum antiviral properties along with a much higher genetic barrier to drug resistance. Cyclin-dependent kinases (CDKs) represent one such host factor. In this review, we summarized a number of CDK inhibitors (CDKIs) of varied chemical scaffolds with demonstrated antiviral activity. Challenges and issues associated with the repurposing of CDKIs as antiviral agents were also discussed.