Objective To observe the clinical efficacy of Fuzheng Xiaoji granules combined with first-line chemotherapy in colorectal cancer patients with stasis toxin internal obstruction syndrome and the influence of gut microbiota in them. Methods A total of 100 stage Ⅳ colorectal cancer patients with stasis toxin internal obstruction syndrome admitted to Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from January 1, 2019 to December 31, 2023 were selected as the study subjects. They were randomly divided into a control group and a treatment group using a random number table method, with 50 cases in each group. The control group received standard Western medicine chemotherapy, and the treatment group was given modified oral Fuzheng Xiaoji granules combined with chemotherapy. Six months later, the traditional Chinese medicine syndrome scores and Kanofsky performance score (KPS) of the two groups before, during, and after treatment were compared between the two groups, and the gut microbiota were compared between the two groups. Results Before treatment, the traditional Chinese medicine syndrome scores and KPS of the two groups were similar, and the difference was not statistically significant (both P>0.05). After treatment, the scores of depression, anxiety, and fatigue in the treatment group decreased compared to those before treatment (all P<0.05). Tingling, localized pain, refusal to press, depression and anxiety, and fatigue in the treatment group decreased compared with those in the control group (all P<0.01). The symptoms in the control group were similar, and the difference was not statistically significant (all P>0.05). The results of two groups of gut microbiota showed a slight increase in the abundance of gut microbiota in the control group compared to the treatment group. The differential microbiota with linear discriminant analysis (LDA) values>2 in the two groups were Actinobacteria, Ruminococcus, Clostridium, Campylobacter, Abiotrophya, Chloroplast, and Pseudomonas in the control group, and Aeromonas in the treatment group. Conclusions The combination of Fuzheng Xiaoji granules and first-line chemotherapy can improve the quality of life of colorectal cancer patients with stasis toxin internal obstruction syndrome, regulate the patient's gut microbiota, and improve traditional Chinese medicine symptoms.