Objective <p>To investigate the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) combined with anlotinib and immunotherapy as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) and liver metastases.</p> Methods <p>This single-center, retrospective study enrolled patients with advanced NSCLC and liver metastases who experienced disease progression after first-line first‑line chemoimmunotherapy and subsequently received second-line treatment with nab-paclitaxel plus anlotinib and a PD-1/PD-L1 inhibitor between January 2021 and April 2024. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).</p> Results <p>A total of 32 patients were included in the analysis. The combination regimen demonstrated notable antitumor activity, with an ORR of 25.00% (8/32) and a DCR of 53.13% (17/32). The median PFS was 4.0 months (95% CI: 4.05–4.64), and the median OS was 9.0 months (95% CI: 8.38–9.49). Subgroup analysis indicated that patients who experienced treatment-related AEs such as hypertension, proteinuria, or hand-foot syndrome achieved better therapeutic outcomes than those who did not. Exploratory biomarker analysis suggested that the regimen may exert synergistic antitumor effects by modulating immune cell profiles and alleviating immunosuppression. The safety profile was generally manageable, with most AEs being mild to moderate in severity, indicating favorable tolerability.</p> Conclusion <p>The combination of nab-paclitaxel, anlotinib, and immunotherapy appears to be a feasible and effective second-line treatment option for advanced NSCLC patients with liver metastases, offering comparable efficacy with acceptable toxicity. These findings warrant validation in prospective, randomized controlled trials.</p>