Intestinal barrier integrity is fundamental to the maintenance of body homeostasis. The mechanosensitive ion channel Piezo1, acting as a pivotal hub for mechanical signal transduction, converts mechanical stimuli into biochemical signals and plays a central role in the regulation of the intestinal barrier. This review systematically delineates the basic structure and kinetic properties of Piezo1 and comprehensively elaborates on its macro-regulatory functions across the multidimensional network of the intestinal mechanical, chemical, biological, and immune barriers. Furthermore, it investigates the mechanistic association between Piezo1-mediated mechanical signaling abnormalities and the pathogenesis of digestive system barrier dysfunction disorders, as well as potential targeted intervention strategies. By summarizing current research on Piezo1 and intestinal barrier function, this review aims to provide novel perspectives for elucidating the pathogenesis and advancing clinical targeted therapies for intestinal barrier dysfunction disorders.