Novel antibiotic substitutes are increasingly in demand in the animal husbandry industry. An oral recombinant Lactococcus lactis (L. lactis) expressing human LL-37 (oral LL-37) was developed and its safety and antiviral effectiveness in vivo was tested. In addition to impairing liposome integrity, LL-37 polypeptide from recombinant L. lactis could prevent the host cell infection by a variety of viruses, including recombinant SARS, SARS-CoV-2, Ebola virus, and vesicular stomatitis virus G. Subchronic toxicity studies performed on Sprague-Dawley rats showed that no cumulative toxicity was found during short-term intervention. Oral LL-37 treatment after the onset of fever could reduce mortality in piglets infected with porcine reproductive and respiratory syndrome virus. Moreover, body weight gain of piglets receiving treatment was progressively restored, and nucleic acid positive rebound was not undetected after discontinuation. Oral LL-37 consistently increased the lifespan of chickens infected with Newcastle viruses. These findings suggested a potential use of recombinantly modified microorganisms in veterinary medicine.