Objective To compare and observe the effect of the recombinant human endostatin (Endostar) combined with chemotherapy in treatment of advanced colorectal cancer. Methods A total of 132 patients with advanced colorectal cancer were divided into Endostar combined with chemotherapy group (experimental group, 66 cases) and chemotherapy group (control group, 66 cases). FOLFOX4 or FOLFIRI was adopted for chemotherapy. The clinical effect of the two groups were observed and compared, and patients were followed up for survival. Results ① The objective response rate (ORR) of experimental groupand control group was 21.2% and 18.2%, respectively, which was not statistically different (P > 0.05); the disease control rate (DCR) was respectively 71.2% and 50%, which was statistically different (P = 0.013). Compared with the control group, one-year survival rate (58.5% vs 46.4%), two-year survival rate (24.3% vs 18.0%) and the median survival time (16 months, 95% CI: 10.550, 21.450 vs 12 months, 95% CI: 9.062, 14.938) of experimental group were significantly higher and longer (P = 0.048). ② The one-year survival rate (56% vs 37.8%), two-year survival rate (32.1% vs 15.8%) and median survival time (16 months, 95% CI: 8.558, 23.442 vs 10 months, 95% CI: 5.460, 14.540) of Endostar plus FOLFIRI therapy were statistically significantly higher and longer than those of FOLFIRI therapy (P = 0.018). ③ One-year and two-year survival rates of 2-3 cycles and 4-6 cycles were 22.8% vs 72.4% and 10.8% vs 32.1%, respectively. The median survival time was 6 months (95% CI: 2.862, 9.138) and 20 months (95% CI: 16.511, 23.489), respectively. The survival advantage of 4-6 cycles was statistically significant (P < 0.05). Conclusion Recombinant human endostat in (Endostar) combined with chemotherapy for advanced colorectal cancer has a higher DCR and a longer median survival time than chemotherapy alone. It can improve the 1-year and 2-year survival rates without significantly increasing toxicity and side effects, which is worthy of further clinical study and application.