Testing approved antivirals against A(H5N1) influenza viruses circulating in peridomestic species, including dairy cows, is critical to public health and pre-pandemic planning. It cannot be tested in humans due to A(H5N1) disease severity. Here, in mice, we demonstrate that US FDA-approved baloxavir treatment mediates improved disease outcomes (survival and viral dissemination) over oseltamivir after lethal intranasal and ocular challenge with A(H5N1)-contaminated cow milk.