Abstract: Covalent inhibitors can realize specific binding by forming covalent bonds with the target, which can realize long-lasting inhibition of the target while reducing the dosage, and to a certain extent, they have overcome the traditional targets that are difficult to become drugs, and they have shown unique advantages in drug discovery and development. The binding characteristics of covalent inhibitors to plasma proteins are closely related to the efficacy, in vivo metabolism, and toxic side effects of these drugs, but the current research in this field is still limited, and there is a lack of systematic studies on the binding of covalent inhibitors of different warheads to high abundance proteins in human blood. Meanwhile, mass spectrometry has become an important tool to characterize the binding of covalent inhibitors to plasma proteins, and mass spectrometry-based proteomics can be used to comprehensively investigate the binding rate, binding reversibility, binding influencing factors, binding protein species, and binding sites of covalent inhibitors to plasma proteins. In this paper, the warheads of covalent inhibitors, the binding characteristics of covalent inhibitors to blood proteins and the research progress of mass spectrometry in the binding of covalent inhibitors to plasma proteins in recent years are reviewed to provide a reference for the study of binding of this class of drugs to plasma proteins.