Despite the well-documented historical importance of polyploidy, the mechanisms responsible for the establishment and evolutionary success of novel polyploid lineages remain unresolved. One possibility, which has not been previously evaluated theoretically, is that novel polyploid lineages are initially more resistant to pathogens than the diploid progenitor species. Here, we explore this possibility by developing and analysing mathematical models of interactions between newly formed polyploid lineages and their pathogens. We find that for the genetic mechanisms of pathogen resistance with the best empirical support, newly formed polyploid populations of hosts are expected to be more resistant than their diploid progenitors. This effect can be quite strong and, in the case of perennial species with recurrent polyploid formation, may last indefinitely, potentially providing a general explanation for the successful establishment of novel polyploid lineages.