Invasive annual grasses (IAG) continue to spread within the sagebrush biome of the western United States, degrading plant communities and wildlife habitat, decreasing forage for ranching livelihoods, and heightening wildfire risk. Effective management of IAGs requires action and long-term strategic planning across the sagebrush biome, but the cumulative effects of IAG treatments over time and space are not well understood, especially over broad extents defined for strategies like the Sagebrush Conservation Design. We developed a simulation model and sampling framework that allow local-scale actions to be ‘scaled up’ to evaluate large-scale regional and biome-wide management strategy outcomes. We worked with natural resource managers and experts to co-develop a spatially explicit state-and-transition simulation model of IAG dynamics in sagebrush landscapes that can be used to evaluate alternative management strategies. We evaluated our framework by contrasting two baseline scenarios in terms of their long-term effects on the sagebrush biome. We show that focusing management efforts on moderate to high IAG cover was effective at reducing full conversion to IAGs but failed to prevent widespread establishment of IAGs in core sagebrush areas, exposing them to increased risk of wildfire and wildlife habitat degradation. The results of our model help quantify the extent of the problem that IAGs pose to sagebrush ecosystems given current knowledge and management efforts. Our framework provides a platform to explore alternative management strategy outcomes and can help managers develop informed conservation plans with realistic expectations for return on investment of resources committed to sagebrush landscapes.