Bone metastasis severely affects the life span and quality of life of survivors of lung adenocarcinoma (ADC). There is a pressing need to identify viable biomarkers for this incurable, fatal disease. Spondin-2 (SPON2) has been reported to be involved in metastasis and cancer progression, but its role in bone metastasis in patients with lung ADC has rarely been studied. Here, we showed that the upregulation of SPON2 increased the migration, invasion, and epithelial-to-mesenchymal transition of ADC cells in vitro, whereas silencing SPON2 repressed these processes. Consistently, silencing SPON2 significantly reduced the bone metastasis of ADC cells in vivo. Mechanistically, SPON2 activated the nuclear factor-κB (NF-κB) signaling pathway and increased the expression levels of MMP2 and MMP9. Blocking NF-κB using an inhibitor attenuated the SPON2-induced migration and invasion of ADC cells. In addition, we found that SPON2 expression levels were increased in metastatic bone tissues compared to primary ADC tissues. The upregulation of SPON2 was positively correlated with MMP2 and MMP9 expression levels in metastatic bone tissues. In conclusion, these results illustrate that SPON2 plays a key role in ADC by activating the NF-κB pathway to promote bone metastasis, which suggests that it may be a target for future drug development.