Abstract: Osteoporosis (OP) is characterized by impaired osteoblast activity and excessive bone resorption, yet effective anabolic therapies remain limited. Here, we identify heat shock cognat 71 kDa protein (HSC70) as a novel negative regulator of osteoblast differentiation and reveal echinacoside (ECH), a natural phenylethanoid glycoside from Cistanche deserticola, as its direct inhibitor. Functional studies demonstrated that inhibition or knockdown of Hsc70 promoted osteoblast differentiation and mineralization, while Hsc70 overexpression abrogated the effects of ECH. Mechanistically, ECH suppressed HSC70 activity to activate Wnt/β-catenin signaling, enhance β-catenin nuclear translocation, and improve mitochondrial dynamics, ATP production, and biogenesis, thereby providing metabolic support for osteogenesis. In vivo, ECH treatment and hsc70 knockout alleviated glucocorticoid-induced bone loss and restored mineralization in zebrafish models. Collectively, this work uncovers the HSC70–β-catenin/mitochondrial axis as a druggable pathway for skeletal homeostasis and positions ECH as a promising natural lead for developing bone-anabolic therapies against OP.