Since the outbreak of COVID-19, the pandemic caused by SARS-CoV-2 infection is still spreading at an alarming rate and has caused huge loss of life and economic damage worldwide. Although more than one year has passed, effective treatments for COVID-19 and other pathogenic coronaviruses have not yet been developed. Therefore, the development of SARS-CoV-2 inhibitors is an urgent priority. Given that the M(pro) sequences of SARS-CoV-2 and SARS-CoV-1 are 100% identical in the catalytic domain for protein cleavage, the viral main protease (M(pro)) is one of the most extensive drug targets in all the drug targets being investigated for SARS-CoV-2. To provide scientific researchers with timely anti-SARS-CoV drug development information for M(pro), we focus on the past and current drug design and development strategies for M(Pro) in this review. We believe that this review will provide meaningful guidance for the design and development of innovative drugs against COVID-19 and other pathogenic coronaviruses in the future.