AbstractAs we age, our bones undergo a process of loss, often accompanied by muscle weakness and reduced physical activity. This is exacerbated by decreased responsiveness to mechanical stimulation in aged skeleton, leading to the hypothesis that decreased mechanical stimulation plays an important role in age‐related bone loss. Piezo1, a mechanosensitive ion channel, is critical for bone homeostasis and mechanotransduction. Here, we observed a decrease inPiezo1expression with age in both murine and human cortical bone. Furthermore, loss ofPiezo1in osteoblasts and osteocytes resulted in an increase in age‐associated cortical bone loss compared to control mice. The loss of cortical bone was due to an expansion of the endosteal perimeter resulting from increased endocortical resorption. In addition, expression ofTnfrsf11b, encoding anti‐osteoclastogenic protein OPG, decreases withPiezo1in vitro and in vivo in bone cells, suggesting that Piezo1 suppresses osteoclast formation by promotingTnfrsf11bexpression. Our results highlight the importance of Piezo1‐mediated mechanical signaling in protecting against age‐associated cortical bone loss by inhibiting bone resorption in mice.