Background: Extensive Small-cell lung cancer (ES-SCLC) has a poor prognosis following the failure of first-line therapy based immune checkpoint inhibitors. This study aimed to evaluate the efficacy and safety of nab-paclitaxel combined with anlotinib as second-line treatment for relapsed SCLC. Methods: This retrospective study enrolled patients with relapsed ES-SCLC who experienced disease progression after a prior regimen. Patients were divided into two groups based on received treatment: patients receiving 125 mg/m² of nab-paclitaxel on days 1 and 8, repeated every three weeks for six cycles (the NAP group) and patients receiving 125 mg/m² of nab-paclitaxel on days 1 and 8 accompanied with 12 mg/day of anlotinib for 14 days, repeated every three weeks for up to six cycles, followed by maintenance anlotinib until disease progression or unacceptable toxicity (the ANNAB group). The primary endpoints were progression-free survival (PFS) and overall response rate (ORR). The secondary endpoints were overall survival (OS) and safety. Results: Between January 1, 2023, and July 31, 2024, 48 patients were enrolled into the study. Patients were allocated to either the NAP group or the ANNAB group based on the actual treatment regimen administered as determined by the physician’s clinical assessment and patient discussion. The median PFS was 6.0 months in the ANNAB group and 4.7 months in the NAP group (p = 0.0004). ORR was significantly higher in the ANNAB group than in the NAP group (37.5% vs. 8.3%, p = 0.0363). The median OS was 10.0 months in the ANNAB group compared to 7.3 months in the NAP group (p < 0.0001). There were no significant differences in adverse events between the two groups. Conclusions: The combination of nab-paclitaxel and anlotinib as second-line treatment for recurrent SCLC demonstrated promising efficacy and an acceptable toxicity profile, suggesting its potential as a viable therapeutic strategy.