Antimicrobial peptide resistance has been proposed to play a major role in the flea-borne transmission of Yersinia pestis . However, the antimicrobial peptide response in fleas and their interaction with Y. pestis is largely unknown. Attacins are one of the most abundantly expressed antimicrobial peptides within the first hours after Y. pestis infection of Xenopsylla cheopis , a major vector of plague. In this study, we report the cloning, expression, and purification of two X. cheopis attacin peptides and describe their interactions with and antimicrobial activities against Y. pestis . These flea attacins were shown to bind lipopolysaccharides and have potent activity against Y. pestis , however the mechanism of killing does not involve extensive membrane damage. Treatment with attacins rapidly inhibits Y. pestis colony formation and results in oxidative stress, yet live-cell imaging revealed that bacteria continue to grow and divide for several hours in the presence of attacins before undergoing morphological changes and subsequent lysis. This data provides insights into an early battle between vector and pathogen that may impact transmission of one of the most virulent diseases known to man.