The harlequin ladybird Harmonia axyridis has emerged as a model species in the context of invasion biology and possesses an expanded repertoire of antimicrobial peptides (AMPs). Here we measured the expression of 22 AMP genes in adult beetles from native and introduced populations, and from a biocontrol population, allowing us to compare populations differing in terms of invasive performance. Strikingly, we observed population-specific expression profiles for particular AMPs. Following an immune challenge, the genes for Coleoptericin1 (Col1), Coleoptericin-likeB and Defensin1 were induced up to several thousand times more strongly in the invasive populations compared to the native and biocontrol populations. To determine the role of Col1 in pathogen resistance, the corresponding gene was silenced by RNA interference (RNAi), causing higher mortality in beetles subsequently infected with the entomopathogen Pseudomonas entomophila. The RNAi-triggered susceptibility to this pathogen was reversed by the injection of a synthetic Col1 peptide. We show that a native population is more susceptible to P. entomomophila infection than an invasive population. This is the first study demonstrating population-specific differences in the immune system of an invasive species and suggests that rapid gene expression changes and a highly adaptive immune system could promote pathogen resistance and thereby invasive performance.