Osteoporosis is a metabolic dysregulation of bone that occurs mainly in postmenopausal women, and the hyperfunction of osteoclasts is the primary contributor to postmenopausal osteoporosis. However, the development of effective therapeutic drugs and precise delivery systems remains a challenge in the field of anti-absorption therapy. Here, we reported the α-cyperone (α-CYP) for anti-osteoporosis and developed a liposome-based nano-drug delivery system of α-CYP, that specifically targets the bone resorption interface. Firstly, we found that the α-CYP, one of the major sesquiterpenes of Cyperus rotundus L., attenuated the progression of osteoporosis in ovariectomized (OVX) mice and down-regulated the expression of phosphorylated proteins of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), causing down-regulation of osteoclast-related genes/proteins and curbing osteoclast differentiation. Furthermore, α-CYP reversed the activation of osteoclastic differentiation and enhanced osteoporosis-related proteins expression caused by PI3K/Akt agonist (YS-49). More importantly, we adopted the osteoclastic resorption surface targeting peptide Asp8 and constructed the liposome (lipαC@Asp8) to deliver α-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis. In conclusion, this study demonstrated that α-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway, and the liposome targeting delivery systems loaded with α-CYP might provide a novel and effective strategy to treat osteoporosis.