Piezo ion channels, notably Piezo1 and Piezo2, are key mechanosensors that transduce mechanical forces into intracellular signals, playing indispensable roles in digestive physiology. These channels regulate essential functions such as intestinal motility, epithelial barrier integrity, bile secretion, and host–microbiota balance. Emerging evidence links aberrant Piezo signaling to a wide range of gastrointestinal disorders, including functional bowel diseases, inflammatory conditions, and digestive cancers. However, translating these insights into therapeutic applications remains challenging. Most current findings are derived from animal models or in vitro studies, which do not fully recapitulate human tissue complexity. Advanced human-relevant platforms, such as organoids and organ-on-a-chip systems, are needed to bridge this translational gap. Furthermore, Piezo1 and Piezo2 play both overlapping and distinct roles in gastrointestinal pathophysiology, necessitating selective modulation strategies. While Piezo1 promotes processes such as epithelial remodeling and tumor invasion via pathways like RhoA/ROCK and YAP/TAZ, Piezo2 is more associated with sensory neuron activity, immune modulation, and tumor aggressiveness. The lack of specific agonists and inhibitors, especially for Piezo2, further limits its clinical translation. Lastly, Piezo channels are deeply integrated into complex molecular networks involving focal adhesions, cytoskeletal dynamics, and transcriptional regulation. This review synthesizes current advances in the mechanobiology of Piezo channels within the digestive system and highlights future directions for mechanistically-informed, Piezo-targeted therapies.