Objective: To study the clinical effects of multigene combination test to guide chemotherapy combined with targeted therapy in patients with advanced gastrointestinal tumors. Methods: The samples were selected from 60 patients with advanced gastrointestinal tumors admitted to our hospital from March 2019 to July 2020, and were divided into a study group and a control group using a random number table model; patients in the control group did not undergo genetic testing and FOLLOX4+PD-1 chemotherapy, while patients in the study group underwent TYMS, ERCC1, EGFR, and KRAS and VEGF gene expression levels test, and the sensitive treatment plan was determined based on the test results, and the clinical indexes were compared between the two groups. Results: By comparing the total effective rate, survival time, and time to disease progression of chemotherapy in the two groups, the study group has a significant advantage (P<0.05). Conclusion: The combination of chemotherapy and targeted therapy for advanced gastrointestinal tumor patients can improve the efficiency of chemotherapy and prolong the time of disease progression and survival, which is worthy of comprehensive promotion.