Protein disulfide isomerase (PDI) can catalyze the formation, breakage and rearrangement of disulfide bonds, and promote protein folding, which is essential to stabilize the three-dimensional structure of proteins. The dysregulation of PDI expression or enzyme activity is closely related to a series of diseases, such as cancer, neurodegenerative diseases, and thrombosis. In this review, we summarized the structure of PDI, its relationship with diseases and the research progress of its inhibitors. We also pointed out the current problems and the development direction of PDI inhibitors, which will provide references for its further research.