Globally, invasion by non-native plants threatens resources that nature reserves are designated to protect. We assessed the status of non-native plant invasion on 1,662, 0.1-ha plots in Death Valley National Park, Mojave National Preserve, and Lake Mead National Recreation Area. These parks comprise 2.5 million ha, 23% of the national park land in the contiguous USA. At least one non-native species inhabited 82% of plots. Thirty-one percent of plots contained one non-native species, 30% two, 17% three, and 4% four to ten non-native species. Red brome (Bromus rubens), an ‘ecosystem engineer’ that alters fire regimes, was most widespread, infesting 60% of plots. By identifying frequency of species through this assessment, early detection and treatment can target infrequent species or minimally invaded sites, while containment strategies could focus on established invaders. We further compared two existing systems for prioritizing species for management and found that a third of species on plots had no rankings available. Moreover, rankings did not always agree between ranking systems for species that were ranked. Presence of multiple non-native species complicates treatment, and while we found that 40% of plots contained both forb and grass invaders, exploiting accelerated phenology of non-natives (compared to native annuals) might help manage multi-species invasions. Large sizes of these parks and scale of invasion are formidable challenges for management. Yet, precisely because of their size, these reserves represent opportunities to conserve large landscapes of native species by managing non-native plant invasions.