Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis (OA) development. This study demonstrates that Piezo1, but not Piezo2, is essential for postnatal trabecular bone formation and the development of OA. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1 Col2a1Cre) showed a near absence of trabecular bone below the growth plate and multiple rib fractures at 7 days of age. These mice exhibited reduced OA pathologies compared to littermates at 60 weeks of age, and chondrocyte-specific Piezo1 inactivation attenuated articular cartilage degeneration and osteophyte formation after surgical induction of OA. Additionally, increased Piezo1 protein abundance was observed in cartilaginous zones of human osteophytes. The study identified Ptgs2 and Ccn2 as potentially relevant downstream genes of Piezo1 in chondrocytes. These findings suggest that Piezo1 is a critical regulator of both physiological and pathological endochondral ossification processes and that Piezo1 antagonists may be a novel approach to limit osteophyte formation in OA. The study also highlights the importance of understanding the role of Piezo1 in chondrocytes for developing new therapeutic strategies for OA.Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis (OA) development. This study demonstrates that Piezo1, but not Piezo2, is essential for postnatal trabecular bone formation and the development of OA. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1 Col2a1Cre) showed a near absence of trabecular bone below the growth plate and multiple rib fractures at 7 days of age. These mice exhibited reduced OA pathologies compared to littermates at 60 weeks of age, and chondrocyte-specific Piezo1 inactivation attenuated articular cartilage degeneration and osteophyte formation after surgical induction of OA. Additionally, increased Piezo1 protein abundance was observed in cartilaginous zones of human osteophytes. The study identified Ptgs2 and Ccn2 as potentially relevant downstream genes of Piezo1 in chondrocytes. These findings suggest that Piezo1 is a critical regulator of both physiological and pathological endochondral ossification processes and that Piezo1 antagonists may be a novel approach to limit osteophyte formation in OA. The study also highlights the importance of understanding the role of Piezo1 in chondrocytes for developing new therapeutic strategies for OA.