Pathogen-specific countermeasures cannot be deployed until an emerging virus is identified, whereas much of the burden of a respiratory epidemic accrues beforehand. Host-directed prophylaxis may protect during this interval. We evaluated inhaled dry-powder R27T, a glycoengineered interferon-β (IFN-β) mutein, as pre-exposure prophylaxis in African green monkeys (AGM). A single head-dome exposure delivered quantifiable airway R27T for 24 h, with systemic concentrations ~100-fold lower than after intravenous infusion. Airway MX1, OAS1, and OAS3 induction persisted longer after inhalation than after intravenous delivery. In SARS-CoV-2-challenged AGM, R27T given 24 h before challenge reduced viral RNA by up to 2.7 log₁₀ in bronchoalveolar lavage fluid and 3.5 log₁₀ in lung tissue, and reduced infectious lower-airway virus to at or below the limit of detection. In influenza A-challenged AGM, R27T reduced bronchoalveolar lavage viral RNA by 1.7 log₁₀ at day 1, and no infectious virus was recovered from pre-exposure animals. Neither model showed treatment-related airway inflammation or lung injury. As its mechanism is virus-agnostic, inhaled R27T warrants clinical evaluation as prophylaxis before pathogen-specific countermeasures are available.