Understanding the reliability of FDA-approved antivirals against A(H5N1) influenza viruses circulating in peridomestic species including dairy cows is critical to public health and pre-pandemic planning, but it cannot be modeled clinically due to A(H5N1) disease severity. In mice, we demonstrate baloxavir treatment mediates greater disease outcomes (survival, viral dissemination) than oseltamivir after lethal challenge (orally, intranasally, ocularly) with A(H5N1)-contaminated cow milk.