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Cancer-related fatigue (CRF) is multifactorial and best addressed with a multimodal approach. High-quality evidence supports supervised or home-based aerobic and resistance training to improve fatigue, function, and quality of life. Sleep disturbance perpetuates CRF; cognitive behavioral therapy for insomnia (CBT-I) and structured sleep hygiene (consistent schedule, stimulus control, limiting late caffeine, light exposure) are core components. Concurrently, evaluate and treat reversible contributors—anemia, thyroid dysfunction, pain, depression/anxiety, medication effects (e.g., sedating agents), deconditioning, and nutritional deficits. Teach energy-conservation strategies (prioritize tasks, pacing, planned rest) and consider referral to rehabilitation. Stimulants may have a role for select patients after nonpharmacologic measures are optimized, but evidence is mixed and side effects are common; they should not be first-line. Routine high-dose vitamins/herbals lack evidence and may interact with therapies. Delaying action risks entrenching deconditioning. The APRN coordinates referrals (rehab, sleep medicine, psycho-oncology), sets measurable goals (step counts, strength milestones), and schedules follow-up to adjust the plan based on patient-reported outcomes.