Objective: This study aimed to identify nursing-sensitive risk factors for cancer-related fatigue (CRF) and evaluate their predictive value in patients undergoing radiotherapy.Methods: A prospective cohort study was conducted with 200 adult patients (aged 30–80 years) receiving radiotherapy. Data on demographics, clinical characteristics (tumor type, radiation dose, comorbidities), and psychological status were collected via a multidimensional questionnaire. Fatigue severity was measured using the validated Fatigue Severity Scale (FSS). Multiple linear regression analysis was performed (SPSS 29.0; p < 0.05).Results: 35% of patients experienced moderate to severe fatigue. The regression model identified age (β=0.32), female gender (β=0.25), advanced solid tumors (β=0.29), higher radiotherapy dose (β=0.28), and comorbidity count (β=0.21) as significant independent predictors (p < 0.05). The model explained 65% of the variance in fatigue severity (R^2 = 0.65). Stratified analysis showed that fatigue was significantly correlated with psychological distress, particularly in female and advanced-stage patients.Conclusion: Specific demographic and clinical factors are strong predictors of CRF. These findings underscore the necessity of routine screening and tailored nursing interventions for high-risk patients during radiotherapy.