Abstract: Metalloproteins, which play a central role in key processes such as viral replication, assembly, and invasion of host cells, have emerged as ideal targets for antiviral drug design. This article provides a comprehensive review of the latest advances (2021-2023) in antiviral drug research targeting metalloproteins from the perspective of medicinal chemistry, meticulously analyzing metalloprotein inhibitors for important viruses including HIV-1, HCMV, HBV, IFV, RVFV, and SARS-CoV-2, discussing their pharmacological activity, mechanisms of action, and potential for clinical application, addressing the challenges in designing viral metalloenzyme inhibitors, including ensuring high selectivity and specificity, drug stability, bioavailability, and combating drug resistance arising from the high mutation rates of viruses, and summarizing the emerging trends in antiviral drug development, including structure-based drug design, high-throughput screening, fragment growth and multi-site binding strategies, aiming to provide some new avenues and methodologies for the development of novel antiviral drugs that are both potent and less toxic.