Objective: To evaluate the clinical efficacy and safety of apatinib in patients with advanced gastric cancer after the failure of second-line chemotherapy. Methods: From September 2015 to August 2018, 40 patients with advanced gastric cancer who failed second-line chemotherapy were divided into a treatment group and a control group according to whether they were treated with apatinib or not. The treatment group was treated with apatinib, while the control group was treated with optimal support therapy. The objective efficacy and safety of apatinib in patients with advanced gastric cancer were evaluated by comparing the short-term and long-term efficacy and the incidence of adverse reactions between the 2 groups before and after the treatment. Results: In the short-term curative effect observation, the objective remission rate (ORR), disease control rate (DCR) were better than those of the control group, and the differences of DCR were statistically significant (80% vs 20%, P<0.05). In the long-term curative effect index, the median overall survival (OS) of the treatment group was 6.1 months, the median PFS was 3.0 months, the median OS of the control group was 3.7 months, and the median PFS was 1.8 months. The OS and PFS in the treatment group was also superior to those of the control group (P<0.05). Conclusion: The apatinib treatment regimen after the failure of second-line chemotherapy in patients with advanced gastric cancer has a more reliable clinical efficacy and safety. Some patients delay the disease process, the quality of life has improved, the survival time is prolonged to a certain extent, and the clinical benefits are more significant. At the same time, the adverse drug reactions are mild, and most of the patients have good drug tolerance.