Purpose <p>To investigate the effect of an 8-week multi-modal eHealth cancer-related fatigue intervention in women with breast cancer.&#xa0;eHealth included remote education, individualized exercise, and weekly problem-solving sessions. Primary outcomes were recruitment/retention and cancer-related fatigue level. Quality of life was a secondary aim.</p> Methods <p>Women with Stage 0–3 breast cancer between 18–70&#xa0;years who scored ≥ 4/10 on the One-Item Fatigue Scale, completed chemotherapy and/or radiation within 5&#xa0;years, and did not have chronic fatigue, were randomly assigned to eHealth intervention (eHealth) (<i>n</i> = 18) or control (<i>n</i> = 24). Cancer-related fatigue and quality of life were measured before and after intervention using the Brief Fatigue Inventory and the Functional Assessment Cancer Therapy-General.</p> Results <p>Social media was an effective way to recruit participants into this study; however, more participants in the eHealth group dropped out than the control group. Both&#xa0;groups' fatigue scores significantly decreased over time (<i>p</i> = 0.001). eHealth decreases in fatigue reached a minimally clinically important difference (2.25), but control did not (1.3). Quality of life significantly improved in the eHealth group compared to the control (<i>p</i> = 0.03).</p> Conclusion <p>Multi-modal cancer-related fatigue eHealth intervention appears to clinically reduce fatigue and improve quality of life among women with breast cancer.</p> <p>US Clinical Trial Register NCT05868187. Date registered: 2–7-2023. <a href="http://www.clinicalgrials.gov">www.clinicalgrials.gov</a></p>