Daptomycin is an important antibiotic for the treatment of infections caused by . The emergence of daptomycin resistance in is associated with treatment failure and persistent infections with poor clinical outcomes. Here, we investigated host innate immune responses against clinically derived, daptomycin-resistant (DAP-R) and -susceptible paired isolates using a zebrafish infection model. We showed that the control of DAP-R infections was attenuated in vivo due to cross-resistance to host cationic antimicrobial peptides. These data provide mechanistic understanding into persistent infections caused by DAP-R and provide crucial insights into the adaptive evolution of this troublesome pathogen.