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The emergence of multidrug resistant bacteria is a global health threat and the discovery of new antimicrobial agents is an absolute priority. In this context endogenous peptides are emerging as novel potential candidates. In this work, we assessed the antimicrobial effects of orexins and ghrelin neuropeptides against gram-negative (Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae) and gram-positive (Staphylococcus aureus) bacteria. Orexin-B and ghrelin showed a potent bactericidal effect at concentration equal to or greater than 25 μg/ml. No antimicrobial activity has been observed for orexin-A. Furthermore, we investigated the antiviral proprieties of the three peptides against herpes simplex virus 1 (HSV-1). We found that orexin-B, but not orexin-A is effective for HSV-1 infectivity inhibition.