Purpose: Fatigue is a component of frailty and may undermine functional well-being and independent living. The prevalence of fatigue and its impact on functional limitations among older adults with cancer remains understudied. Methods: Using participants enrolled in the Cancer and Aging Resilience Evaluation (CARE), a prospective registry of patients (≥ 60 years) with cancer, who underwent a geriatric assessment (GA) at the first visit with oncology, we examined the presence of fatigue based on self-report of moderate to severe fatigue on PROMIS global health 10-item instrument at the time of GA. We examined the association of fatigue with impairments in instrumental activities of daily living (IADL) and activities of daily living (ADL) adjusting for age, sex, race/ethnicity, education, cancer type and stage, pain, comorbidities, and time from cancer. Results: We included 374 older adults with cancer with a median age of 70 years; 56% were male and 23% black. Diagnoses included colorectal (33%) and pancreatic cancers (25%), with most patients with advanced stage disease (71% stage III/IV). Overall, 210 (58%) patients reported significant fatigue. Patients reporting significant fatigue had an increased odds of IADL (adjusted odds ratio, aOR 1.9; 95% CI 1.1–3.2) or ADL impairment (aOR 3.6; 95% CI 1.4–9.3), as compared to those without, after adjusting for aforementioned confounders. Conclusions: Over half of older adults with cancer reported moderate to severe fatigue that was independently associated with functional status limitations. Further understanding of the multifaceted aspects of fatigue and development of interventions combating fatigue in this population is urgently needed.