Objective To analyze and preliminarily verify key genes and pathways in the transcriptome of peripheral blood of lung adenocarcinoma patients with metastasis bone pain (MBP), and to explore its underlying mechanism. Methods Nine lung adenocarcinoma patients with bone metastasis treated in the First Affiliated Hospital of Sun Yat-sen University from May 2020 to May 2021 were selected for retrospective analysis, including 4 patients with typical MBP clinical manifestations and visual analogue scale (VAS) ≥4 (MBP group) and 5 patients without suffering any pain (control group). Peripheral blood mRNA sequencing was performed to identify differentially expressed genes (DEGs), followed by functional pathways analysis and protein-protein interaction (PPI) network analysis. The most significant modules and hub genes were confirmed and visualized using Cytoscape software. The target miRNAs regulating these hub genes were predicted using Targetscan database, and long non-coding RNA (lncRNA) interacting with these miRNAs were also predicted using lncBase database. The relationships among lncRNA, miRNA and mRNA were visualized to construct a competing endogenous RNA (ceRNA) network through Cytoscape software, and the nodes of this network were verified using quantitative PCR (qPCR). Results A total of 1466 DEGs were identified, including 666 up-regulated genes and 800 down-regulated genes. Chemokine receptor 3 (CXCR3), pro-opiomelanocortin (POMC), neuromedin U receptor 1 (NMUR1), chemokine ligand 2 (CCL2) and endocannabinoid receptor 1 (CNR1) were identified as hub genes. The most significant enriched processes and pathways of DEGs included osteoclast differentiation, NOD like receptor signal transduction pathway, type Ⅰ interferon signal pathway, nuclear factor kappa-B (NF-κB) signal pathway, apoptosis/autophagy pathway, chemokine signal pathway, interleukin (IL)-1β pathway. Two ceRNA networks were identified: MALAT1-hsa-miR-124-3p.2-CCL2 and NEAT1-hsa-miR-325-3p-CXCR3. qPCR results showed that the expression levels of CCL2, CXCR3, MALAT1, NEAT1 and hsa-miR-325 were higher in MBP group than these in control group (P<0.05). Conclusions CXCR3, POMC, NMUR1, CCL2 and CNR1 may serve as key genes in the occurrence of MBP and could be important regulatory targets for MBP. The development of MBP in lung adenocarcinoma may be associated with the dysregulation of the networks: MALAT1-hsa-miR-124-3p.2-CCL2 and NEAT1-hsa-miR-325-3p-CXCR3.