Aim: Brain metastases (BM) in patients with lung cancer (LC) are linked to unfavorable outcomes. The eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) is notably overexpressed across various cancer types and plays a role in promoting tumor initiation and progression. This research aimed to clarify the function of EEF1A2 in the context of lung cancer brain metastasis (LCBM) and to explore the mechanisms underlying its effects. Methods: To identify genes with differential expression between LC and LCBM samples, transcriptomic microarray analyses were conducted, confirming that EEF1A2 expression is elevated in LCBM. EEF1A2 expression levels were validated in multiple LC cell lines. PC9 and SPCA1 cells were transfected with lentiviral vectors carrying siRNAs targeting EEF1A2 to assess its role both in vitro and in vivo. Tandem mass tag proteomics was employed to identify proteins regulated by EEF1A2. The expression of EEF1A2, BCL10, and phosphorylated NF-kappa B in tumor tissues from LC and LCBM patients was analyzed. Results: Compared to the LC samples, the LCBM samples exhibited significantly higher levels of EEF1A2 expression. EEF1A2 knockdown in PC9 and SPCA1 cells resulted in substantial reductions in cell proliferation, migration, and invasion. Proteomic profiling revealed that BCL10 protein levels were markedly reduced in EEF1A2knockdown cells. Additionally, there was a decrease in phosphorylated NF-kappa B, EGFR, and mesenchymal markers (N-cadherin, Twist, Snail, Slug, and Cdc42), along with an increase in E-cadherin expression. In a mouse model, EEF1A2 knockdown in PC9 cells significantly inhibited brain metastasis. Furthermore, patient samples presented elevated levels of EEF1A2, BCL10, and phosphorylated NF-kappa B in LCBM tissues than in LC tissues. Conclusion: Our research revealed that EEF1A2 is upregulated in LCBM, and that its knockdown suppresses brain metastasis by decreasing BCL10 expression, inhibiting NF-kappa B signaling, and reducing epithelial-mesenchymal transition markers. These results suggest that targeting EEF1A2 may be a promising therapeutic approach for preventing and treating brain metastasis in lung cancer patients.