The lysosomal-related protein NPC2 affects the occurrence and development of tumors in terms of stemness, gene mutational burden, and microsatellite instability of tumor cells. Here, combining with our previous scRNA-seq data, we identified the protective role of NPC2 in bone metastasis of lung adenocarcinoma (LUAD). Bone metastases exhibited lower NPC2 expression compared to primary tumors, and low NPC2 expression was associated with poorer LUAD patient survival. NPC2 knockdown LUAD cells exhibited enhanced migration capability, and their supernatant accelerated the osteoclast differentiation and maturation. In vivo, NPC2 knockdown promoted the development of osteolytic lesions induced by PC9 cells, whereas NPC2 overexpression partially rescued these lesions. We also found that these effects might be mediated via the AKT/mTOR signaling pathway and crosstalk between cancer cells and osteoclasts. These findings indicate that NPC2 plays a critical role in the osteolytic metastasis of LUAD and may represent a promising therapeutic target for this disease.