Abstract: Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused extremely serious impact on human life and health as well as social and economic development. The ongoing mutation of the virus poses a significant public health risk by limiting the effectiveness of current vaccines and drugs. Therefore, there is an urgent need to discover drugs with new targets and new mechanisms to combat potential pandemics caused by mutant viruses. S protein is an important surface protein of SARS-CoV-2 that mediates the critical step of viral invasion into host cells. Spike proteins play a crucial role in viral entry and are considered attractive targets for antiviral drugs. By analyzing the research examples of S protein inhibitors in recent years, this paper summarizes the progress made in this field, aiming to provide a reference for the research and development of anti-SARS-CoV-2 drugs.