Abstract: Objective To assess the effectiveness and adverse reactions of anlotinib combined with hypofractionated radiotherapy in the treatment of non-small cell lung cancer with brain metastasis. Methods A total of 63 non-small cell lung cancer patients with brain metastasis who were admitted to Xuzhou Cancer Hospital from June 2018 to October 2020 were selected and their data were collected for retrospective analysis. They were divided into two groups based on their corresponding treatment: a combined treatment group receiving anlotinib combined with hyperfractionated radiotherapy and a single radiotherapy group receiving hypofractionated radiotherapy alone. The combined treatment group was additionally administered with 12 mg/d anlotinib daily on the basis of hypofractionated radiotherapy for two treatment cycles (with two weeks followed by one week interval per cycle). Then, the clinical effectiveness and adverse reactions of the two groups were observed for analysis. Results The objective remission rate and disease control rate of the combined group were 83.33% and 93.33%, which were statistically higher than those of the single radiotherapy group, 60.61% and 69.70% (P<0.05). Both groups presented radiation brain edema, nerve injury, nausea and vomiting, and other adverse reactions, where patients in the combined group also showed hypertension and clinical hand-foot syndrome, which were all tolerable. The incidence of adverse reactions was 30.00% for the combined group, which was statistically lower than 54.55% in the control group (P<0.05).The 1-year intracranial progression-free survival rate and overall survival rate of the combined treatment group were 80.00% and 76.67%, respectively, which were significantly higher than 54.55% and 51.52% in the single radiotherapy (P<0.05). Conclusions Anlotinib combined with hypofractionated radiotherapy has good therapeutic effect and few adverse reactions in the treatment of non-small cell lung cancer patients with brain metastasis, which is worthy of clinical application.