Abstract: Poxvirus is the largest and most complex virus of the known virions, and the main pathogenicity to humans is Orthopoxvirus. In recent years, with the deep understanding of the biological structure and replication cycle of Orthopoxvirus, new small molecular compounds with high efficiency and low toxicity have been discovered as new drugs, and some have entered the clinical trial stage. This article summarizes the research progress of poxvirus inhibitors with different targets.