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Acute myeloid leukemia (AML) primarily affects older adults, many of whom are unsuitable for intensive chemotherapy. Hypomethylating agents (HMA) -intravenous (IV) decitabine and subcutaneous (SC) azacitidine- are standard therapeutic options but require frequent hospital visits and substantial healthcare resource use. Oral decitabine/cedazuridine (DEC-C) offers a therapeutically equivalent alternative that may reduce hospital resource burden and improve patient convenience. This study estimated and compared the economic and organizational impact of IV, SC, and oral HMA administration in AML patients unfit for standard intensive chemotherapy, from the perspective of the Spanish National Health System. A micro‑costing model quantified direct non‑pharmacological costs associated solely with the administration route across five domains: drug preparation and administration, treatment‑related hospitalizations, medical transportation, catheter management, and infections. Resource use was derived from a survey of 30 healthcare professionals across 16 hospitals and valued using official tariffs. Costs were calculated separately for induction and subsequent cycles; drug acquisition costs were excluded. Non‑pharmacological costs per patient were €9,998 for IV decitabine, €12,177 for SC azacitidine, and €1,306 for oral DEC‑C, representing cost reductions of 87% and 89% for oral therapy versus IV and SC, respectively. Savings were driven mainly by reductions in hospitalization (58-61%), transport (13-22%), infections (9%-12%), administration‑related activities (11-12%) and the avoidance of catheter-related costs. Oral therapy also markedly reduced resource utilization, including 40-50 fewer hours of healthcare professional time, 8-9 fewer inpatient days, and 4-8 fewer ambulance transfers per patient. Catheter use decreased by 33%, and infection risk declined by 87% versus IV and 54% versus SC. Oral administration substantially reduces direct non‑drug costs and frees hospital capacity, offering meaningful organizational efficiencies and contributing to the sustainability of AML care within a resource‑constrained health system. These findings reinforce the value of integrating oral HMAs into clinical pathways.