Objective: To analyze the effect of apatinib, S-1 combined with paclitaxel perfusion on malignant seroperitoneum of gastric cancer. Methods: From December 2019 to May 2020, 172 patients with gastric cancer treated in our hospital were randomly divided into two groups: observation group and control group, 86 cases each. The control group adopted the method of S-1 combined with paclitaxel perfusion therapy in the treatment of malignant seroperitoneum of gastric cancer. The observation group was given oral apatinib on the basis of S-1 combined with paclitaxel perfusion therapy, and the dosage was 500 mg/d. Results: The total effective rate of treatment in the control group was 43.02%, while the total effective rate in the observation group was 69.77%; the drug resistance of the two groups of patients increased and the adverse reactions were low. Conclusion: Apatinib and S-1 combined with paclitaxel perfusion therapy can effectively improve the treatment effect, stabilize the patient's condition, increase the patient's drug resistance to adverse reactions, and have a good prognosis.