C-type natriuretic peptide (CNP) is an endocrine factor that potently promotes long bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side. However, its signaling pathway is unclear in growth plate chondrocytes. We have recently developed an original method for live imaging of intracellular Ca²⁺ in growth plate chondrocytes and found a pathway in which spontaneous Ca²⁺ fluctuations mediated by transient receptor potential cation channel subfamily M member 7 (TRPM7) promotes bone growth. In the present study, our Ca²⁺ imaging data indicated that CNP potentiated spontaneous Ca²⁺ fluctuations in growth plate chondrocytes. Further pharmacological analyses suggested that CNP induced hyperpolarization mediated by big-conductance Ca²⁺-dependent K⁺ (BK) channels, activating TRPM7-mediated Ca²⁺ entry. Indeed, ex vivo organ culture analysis indicated that CNP-facilitated bone growth was abolished by chondrocyte-specific Trpm7 gene ablation. Collectively, we proposed a new CNP signaling axis by which CNP promotes bone growth by activating intracellular Ca²⁺ signaling. These findings might contribute to the development of chemical drugs not only for developmental disorders but also for the artificial modification of body sizes in farm and pet animals.