Endothelial tight junction proteins play an important role in maintaining the integrity of vascular endothelial structure and physiological function. In recent years, studies have found that alterations in the expression, distribution, and structure of endothelial tight junction proteins may lead to many related vascular diseases and pathologies (such as diabetes, atherosclerosis, neurodegenerative diseases, and hypertension). Therefore, related strategies to prevent and/or tight junction proteins dysfunction may be an important therapeutic target. Occludin, as the most representative one among tight junction proteins, is mainly responsible for sealing intercellular junctions, maintaining cell permeability and the integrity of vascular endothelium. Here, we review the published biological information of occludin. We highlight the relationship between occludin and vascular endothelial injury-related disease. At the same time, we show our current knowledge of how vascular endothelial occludin exerts the protective effect and possible clinical applications in the future.