Abstract Background As colorectal cancer (CRC) survivorship increases, so does the challenge of managing cancer-related fatigue, a prevalent condition that severely impacts survivors’ ability to work and overall quality of life. This study delves into the relationship between lifestyle behaviors, assessed using the HEALTHY lifestyle score, and its influence on fatigue among CRC patients. Methods Data was derived from MIRANDA, a multicenter cohort study that enrolls adult CRC patients during a 3-week in-patient rehab within a year after primary CRC treatment. Up to date, n = 438 participants provided information on lifestyle factors at the rehabilitation start (baseline) and then every three months for the first year. The predictors were the HEALTHY lifestyle score and its components (diet, alcohol consumption, physical activity, BMI, and smoking status) calculated at three time points: before surgery, after surgery, and 12 months following rehabilitation. The outcome was fatigue, assessed using the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F-FS) scale. Results Participants with a higher HEALTHY lifestyle score after CRC surgery had statistically significantly lower fatigue levels. The components that contributed most to this finding were smoking and physical activity. Participants who engaged in exercise post-surgery or did not smoke before their cancer diagnosis experienced lower fatigue levels during rehabilitation. Conclusions Lifestyle modifications, such as increasing physical activity and smoking cessation, are crucial in preventing or reducing fatigue among CRC patients. Tailored public health initiatives that advocate for these lifestyle adjustments and their incorporation into CRC rehabilitation protocols could significantly advance survivor care, ultimately leading to better health outcomes. Key messages • The HEALTHY score is associated with fatigue of CRC patients during rehabilitation, highlighting the crucial role of lifestyle changes after CRC treatment. • Smoking cessation and physical activity programs may be the most effective measures for decreasing the fatigue burden of these patients.