Regeneration is an essential demographic step that affects plant population persistence, recovery after disturbances, and potential migration to track suitable climate conditions. Challenges of restoring big sagebrush (Artemisia tridentata) after disturbances including fire-invasive annual grass interactions exemplify the need to understand the complex regeneration processes of this long-lived, woody species that is widespread across the semiarid western U.S. Projected 21st century climate change is expected to increase drought risks and intensify restoration challenges. A detailed understanding of regeneration will be crucial for developing management frameworks for the big sagebrush region in the 21st century. Here, we used two complementary models to explore spatial and temporal relationships in the potential of big sagebrush regeneration representing (1) range-wide big sagebrush regeneration responses in natural vegetation (process-based model) and (2) big sagebrush restoration seeding outcomes following fire in the Great Basin and the Snake River Plains (regression-based model). The process-based model suggested substantial geographic variation in long-term regeneration trajectories with central and northern areas of the big sagebrush region remaining climatically suitable, whereas marginal and southern areas are becoming less suitable. The regression-based model suggested, however, that restoration seeding may become increasingly more difficult, illustrating the particularly difficult challenge of promoting sagebrush establishment after wildfire in invaded landscapes. These results suggest that sustaining big sagebrush on the landscape throughout the 21st century may climatically be feasible for many areas and that uncertainty about the long-term sustainability of big sagebrush may be driven more by dynamics of biological invasions and wildfire than by uncertainty in climate change projections. Divergent projections of the two models under 21st century climate conditions encourage further study to evaluate potential benefits of re-creating conditions of uninvaded, unburned natural big sagebrush vegetation for post-fire restoration seeding, such as seeding in multiple years and, for at least much of the northern Great Basin and Snake River Plains, the control of the fire-invasive annual grass cycle.