Objective: To explore the effect of KAP intervention mode on resilience and cancer-related fatigue in patients with colorectal cancer undergoing chemotherapy. Methods: A prospective randomized trial was conducted. 55 patients with colorectal cancer who received routine nursing from February 2018 to February 2019 were included in the control group, and 55 patients who received routine nursing + KAP intervention from March 2019 to March 2020 were included in the observation group. The scores of Resilience Scale and cancer-related fatigue scale (CFS) before and 6 months after intervention were compared between the two groups. Results: After 6 months of intervention, the score of resilience of the two groups was higher than that before intervention, and that of the observation group was higher than that of the control group, the difference was statistically significant (P < 0.05); The CFS score of the two groups was lower than that before intervention, and that of the observation group was lower than that of the control group, the difference was statistically significant (P < 0.05). Conclusion: KAP intervention model can improve the resilience of patients with colorectal cancer chemotherapy, reduce cancer-related fatigue.