The craniofacial complex functions as a complex mechanosensory system, where specialized tissues continuously convert mechanical stimuli into biochemical signals through mechanotransduction. The mechanosensitive Piezo ion channels, Piezo1 and Piezo2, are critical mediators of this process. This review synthesizes the emerging roles of Piezo channels in craniofacial and dental physiology, including craniofacial bone development, dental stem cell regulation, and orofacial sensation. Furthermore, we discuss their roles in periodontal remodeling and orthodontic tooth movement, where they coordinate both bone resorption and formation in the periodontium. While preclinical evidence suggests the therapeutic potential of targeting Piezo channels to treat dental and orofacial diseases, the translation of these findings into clinical practice remains a critical future direction. This review emphasizes the centrality of Piezo-mediated mechanotransduction in craniofacial development and oral diseases, highlighting it as a promising frontier for novel diagnostic and therapeutic strategies.