Lung cancer's propensity for metastasizing to the spine significantly impacts morbidity and mortality. Understanding the impact of somatic mutations on the prognosis of these metastases is crucial for treatment development and optimization. A retrospective analysis was performed on a neurosurgical cohort of 76 patients with lung cancer with spinal metastasis (LCSM) at a single comprehensive cancer center from 2013 to 2023. Data on patient demographics, tumor biomarkers, treatment modalities, and outcomes were collected and analyzed. Of the 76 patients, 72 (95%) had non-small cell lung cancer, predominantly adenocarcinoma (83%). Patients with EGFR (epidermal growth factor receptor) mutations (n = 19, 25%) had an increased median overall survival (OS) of 3.40 years compared with 1.39 years for those without EGFR mutations (p = 0.01) as well as increased median survival after spinal metastasis (1.73 years vs 0.98 years, p = 0.01). Patients with KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations (n = 16, 21%) had a decreased median OS of 0.71 years compared with 2.60 years for those without KRAS mutations (p = 0.03). Napsin A expression was associated with an improved median OS of 5.41 years compared with 1.39 years (p = 0.01), an increased median survival after spinal metastasis (2.29 years vs 0.71 years, p = 0.01), and better postoperative Frankel grades (OR 10.011, p < 0.01) compared with those without expression. Cytokeratin 7 (CK7) expression was associated with decreased OS in an accelerated failure time (AFT) model (time ratio [TR] 0.562, p = 0.025). Targeted therapy was associated with an increased median OS (3.40 years vs 1.28 years, p < 0.01) and an improved median survival after spinal metastasis (1.73 years vs 0.70 years, p < 0.01). In an AFT model, immunotherapy (TR 2.15, p = 0.007) and targeted therapy (TR 2.20, p = 0.001) were associated with improved OS, while spinal radiotherapy was negatively associated with OS (TR 0.46, p = 0.015). Somatic mutations in EGFR and KRAS and expression of napsin A and CK7 significantly influence survival in patients with LCSM. Mutations in EGFR and expression of napsin A, along with targeted therapy, were associated with better patient outcomes, emphasizing the need for personalized treatment strategies to improve survival and neurological function.