Objective: To investigate the clinical efficacy and adverse reactions of anlotinib in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: The clinical data of 45 patients with advanced non-small cell lung cancer who failed in multi-line treatment and poor tolerance to anti-tumor treatment in the affiliated Hospital of Xuzhou Medical University from June 2017 to January 2019 were analyzed retrospectively. The efficacy, progression-free survival (PFS) and adverse reactions of the patients were evaluated comprehensively. Results: A total of 45 patients were enrolled, including 24 cases in a single group and 21 cases in a combination group (17 cases combined with albumin-bound paclitaxel chemotherapy and 4 cases combined with nivolumab immunotherapy). Among the 45 patients, partial remission (PR) accounted for 4.4% (2/45), stable disease (SD) accounted for 88.9% (40/45), progressive disease (PD) accounted for 6.7%. The objective response rate (ORR) was 4.4%, and the disease control rate (DCR) was 93.3%. The median PFS of 45 patients was 3.70 months. The survival rate of patients with different treatment regimens and short-term effects was significantly different from that of patients with short-term efficacy (P<0.05). The results of log-rank test showed that there was significant difference in the survival rate of patients with different treatment regimens and short-term effects. The PFS in the single drug group was 3.30 months, and the PFS in the combination group was 5.30 months. The PFS in the combination group was better than that in the single drug group. The adverse reactions of 45 patients included hypertension, fatigue, thyroid dysfunction, hand and foot syndrome, and so on. The common adverse events of grade 3 included hypertension, myelosuppression and hand and foot syndrome. No adverse events of grade 4 or above were found in this study. Conclusion: Anlotinib has better disease control and survival benefits in advanced non-small cell lung cancer patients with failed second-line treatment, and the adverse reactions are relatively small.