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Background: Art therapy (AT) as supportive care may help patients cope with cancer treatments. This non‐blinded randomized trial assessed the impact of creative AT on severe fatigue and quality of life (QoL) in localized breast cancer patients undergoing irradiation. Material and Methods: 320 patients were randomized to an AT group (ATG; 8 weekly sessions starting during irradiation) or to a standard group (SG). The primary endpoint was severe global fatigue (Functional Assessment of Chronic Therapy Fatigue subscale score <37) at 1 month post‐irradiation. Quality of life (Fact‐B), anxiety/depression (Hospital Anxiety and Depression Scale (HADS)) and different dimensions of fatigue 20‐item Multidimensional Fatigue Inventory (MFI‐20) were assessed at 1, 6 and 12 months post‐irradiation. The secondary endpoints, fatigue among patients treated with chemotherapy, QoL (Fact‐B), anxiety/depression (HADS) and different dimensions of fatigue (MFI‐20) at 1, 6 and 12 months post‐irradiation (with post hoc analysis in patients with treated with chemotherapy) were also assessed. Results: 82% of patients completed ≥8 sessions. Severe initial global fatigue was observed in 43% of patients in each group, and among in 64% of patients whose treatment protocol contained chemotherapy. At 1 month post‐irradiation, 45% in the ATG and 57% of patients in the SG reported severe global fatigue (p = 0.37); among patients with initial severe mental fatigue (MFF), 79% and 44% had improved MFF (p = 0.007) respectively; similarly 79% and 44% with initial poor motivation had better mental motivation (p = 0.03). At 6 and 12 months, social well‐being scores in the ATG were higher (21.3 and 21.4 vs. 19.8 and 19.2, p = 0.05 and p < 0.01) with a significant improvement for patients who had chemotherapy (41% vs. 18%, p = 0.017). A positive association was observed between the number of AT sessions, fatigue and QoL (p < 0.01). Conclusion: AT did not significantly improve global severe fatigue among all cancer participants 1 month after radiation therapy, however it had a positive impact on social well‐being and may improve MFF and motivation. Highlights: Randomized controlled trial assessed the impact of creative Art therapy (AT) on severe fatigue and quality of life in patients with localized breast cancer undergoing irradiationArt therapy did not significantly improve global severe fatigue among all cancer participants 1 month after radiation therapyArt therapy had a positive impact on social well‐being and may improve mental fatigue and motivation [ABSTRACT FROM AUTHOR]