Objective: To explore the clinical effectiveness of exercise interventions for cancer-related fatigue in colorectal cancer (CRC) patients undergoing chemotherapy based on evidence-based evidence. Methods: A total of 76 patients with CRC were prospectively selected, and they were divided into two groups according to different intervention methods. 38 patients in the control group received routine intervention, and the remaining 38 patients in the treatment group were given exercise intervention under evidence-based concept. The cancer-related fatigue (CRF) grading, physical activity status, exercise compliance, quality of life \[Quality of Life Questionnaire Core-30 (QLQ-C30)\] scores and occurrence of exercise-related adverse events were compared between the two groups. Results: After intervention, compared with the control group, the CRF grading in the treatment group was lower(P<0.05). The physical activity compliance rate in the treatment group was higher compared with that in the control group(P<0.05). The treatment group had higher exercise compliance degree(P<0.05). Compared with the control group, the QLQ-C30 symptom field score in the treatment group was lower while the scores of overall health field and functional field were higher(P<0.05). There was no statistical difference in the incidence of exercise-related adverse events between both groups(P>0.05). Conclusion: Exercise intervention under evidence-based concept can significantly reduce the CRF grading in patients with CRC chemotherapy, further improve the physical activity and exercise compliance, and enhance the quality of life.