ObjectivesExtensive‐stage small cell lung cancer (ES‐SCLC) suffering from brain metastases (BM) has a poor prognosis and lacks effective treatment selection. In this study, we explored the efficacy and safety of combination treatment of albumin‐bound paclitaxel (nab‐ptx), anlotinib, and PD‐1/L1 inhibitors for such special population.MethodsA total of 55 patients diagnosed with ES‐SCLC and BM were enrolled in this retrospective study. Patients received a combination therapy consisting of nab‐ptx, anlotinib, and PD‐1/L1 inhibitors. The primary endpoints included overall response rate (ORR), progression‐free survival (PFS), overall survival (OS), and adverse events (AEs).ResultsThe results demonstrated promising efficacy of the combination therapy for such patients, with an ORR of 36.36%, median PFS and OS of 5.0 and 10.0 m, correspondingly. Subgroup analyses indicated that treatment efficacy closely correlated with patients' Ds‐GPA (Diagnosis‐specified Graded Prognosis Assessment) scores. Mechanistic studies revealed that this regimen likely operates by reducing immune suppression to activate immune function, thereby exerting synergistic anti‐tumor effects. The common AEs include decreased appetite, nausea, leukopenia, hypertension, proteinuria, hand‐foot syndrome, peripheral neuropathy, rash, and thyroid toxicity, most of which are generally mild and can be alleviated with symptomatic treatment.ConclusionThe combination of nab‐ptx, anlotinib, and PD‐1/L1 inhibitors exhibited substantial efficacy and acceptable safety in the treatment of BM from ES‐SCLC. This novel therapeutic approach holds promise for improving the outcomes for patients with this challenging disease. Further studies are needed to validate these findings and investigate the long‐term benefits of this combination regimen.