Objective To explore the effect of the Xiaotan Sanjie (XTSJ) Decoction on quality of life of patients with intermediate and advanced gastric cancer. Methods Non-randomized controlled trial was used in the present study, and the patients were divided into XTSJ group and chemotherapy group according to the voluntary principle. The patients in XTSJ group were treated with XTSJ Decoction based on syndrome differentiation (one dose daily, reduce or increase with the severity of symptoms) with patients having advanced gastric cancer taking for at least 3 months and those receiving radical resection taking for at least 6 months. The patients in chemotherapy group were treated with chemotherapy drug fluorouracil for 3 to 6 cycles. The quality of life of patients in the two groups was evaluated by measuring the quality of life questionnaire (QLQ-C30) scores, Karnofsky performance status (KPS) scale, body weight, and the toxicity. Results The quality of life of patients in XTSJ group was significantly improved than that in the chemotherapy group. The XTSJ group was superior to chemotherapy group in improving the fatigue, insomnia, loss of appetite, nausea and vomiting, and emotional symptoms (P<0.05). In addition, the cost of treatment of XTSJ group was significantly lower than that of chemotherapy group (P<0.05), causing no economic burden increase to the family. The overall health statuses were also significantly different between the two groups (P<0.05). The KPS score and body weight managent in the XTSJ group were significantly improved than those in the chemotherapy group (P<0.05). Moreover, the toxic effect of the XTSJ group was significantly lower than that in chemotherapy group (P<0.05). Conclusion Treatment with XTSJ Decoction can improve the quality of life of the patients with intermediate and advanced gastric cancer by maintaining physical condition and body weight and causing milder adverse reaction.