The study investigates the role of Piezo1 expression in chondrocytes in controlling endochondral ossification and osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of *Piezo1* (*Piezo1*^*Col2a1Cre*^) showed a near absence of trabecular bone formation below the chondrogenic growth plate postnatally and multiple rib fractures at 7 days of age. Despite mild skeletal growth impairment, these mice exhibited less pronounced OA pathologies at 60 weeks of age compared to controls. In induced OA models, chondrocyte-specific *Piezo1* inactivation reduced articular cartilage degeneration and osteophyte formation. Increased *Piezo1* protein abundance was observed in cartilaginous zones of human osteophytes, and *Ptg2* and *Ccn2* were identified as potential downstream genes of *Piezo1* in chondrocytes. These findings suggest that *Piezo1* is a critical regulator of physiological and pathological endochondral ossification processes and that targeting *Piezo1* may be a novel therapeutic approach to limit osteophyte formation in OA.The study investigates the role of Piezo1 expression in chondrocytes in controlling endochondral ossification and osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of *Piezo1* (*Piezo1*^*Col2a1Cre*^) showed a near absence of trabecular bone formation below the chondrogenic growth plate postnatally and multiple rib fractures at 7 days of age. Despite mild skeletal growth impairment, these mice exhibited less pronounced OA pathologies at 60 weeks of age compared to controls. In induced OA models, chondrocyte-specific *Piezo1* inactivation reduced articular cartilage degeneration and osteophyte formation. Increased *Piezo1* protein abundance was observed in cartilaginous zones of human osteophytes, and *Ptg2* and *Ccn2* were identified as potential downstream genes of *Piezo1* in chondrocytes. These findings suggest that *Piezo1* is a critical regulator of physiological and pathological endochondral ossification processes and that targeting *Piezo1* may be a novel therapeutic approach to limit osteophyte formation in OA.