Invasive annual grasses can promote ecosystem state changes and habitat loss in the American Southwest. Non-native annual grasses such as Bromus spp. and Schismus spp. have invaded the Mojave Desert and degraded habitat through increased fire occurrence, severity, and shifting plant community composition. Thus, it is important to identify and characterize the areas where persistent invasion has occurred, identifying where subsequent habitat degradation has increased. Previous plot and landscape-scale analyses have revealed anthropogenic and biophysical correlates with the establishment and dominance of invasive annual grasses in the Mojave Desert. However, these studies have been limited in spatial and temporal scales. Here we use Landsat imagery validated using an extensive network of plot data to map persistent and productive populations of invasive annual grass, called hot spots, across the entire Mojave Desert ecoregion over 12 years (2009–2020). We also identify important variables for predicting hot spot distribution using the Random Forest algorithm and identifying the most invaded subregions. We identified hot spots in over 5% of the Mojave Desert mostly on the western and eastern edges of the ecoregion, and invasive grasses were detected in over 90% of the Mojave Desert at least once in that time. Across the entire Mojave Desert, our results indicate that soil texture, aspect, winter precipitation, and elevation are the highest-ranking predictive variables of invasive grass hot spots, while anthropogenic variables contributed the least to the accuracy of the predictive model. The total area covered by hot spots varied significantly among subregions of the Mojave Desert. We found that anthropogenic variables became more important in explaining invasive annual establishment and persistence as spatial scale was reduced to the subregional level. Our findings have important implications for informing where land management actions can prioritize reducing invasive annual persistence and promoting restoration efforts.