Abstract: The SARS-CoV-2 main protease (M^pro) plays a key role in the viral replication cycle, and is an important target for anti-SARSCoV-2 drugs. However, the rapid mutation of the virus has led to drug resistance with M^pro inhibitors, posing a serious threat to global public health. This article summarizes the resistance mechanisms of SARS-CoV-2 M^pro and explores the strategies for the design of new anti-resistant inhibitors. By analyzing the impact of M^pro resistance mutations on the efficacy of existing inhibitors, we summarized various target structurebased anti-resistance drug design methods such as multi-site occupancy, allosteric site development, and covalent binding, and discussed the utility of PROTAC technology in degrading resistant viral proteins, aiming to provide innovative solutions to the drug resistance problem of SARS-CoV-2 M^pro and some reference for drug screening and development in response to potential future coronavirus pandemics.