As climate changes in coming decades, ponderosa pine forest persistence may be increasingly dictated by their regeneration. Sustained regeneration failure has been predicted for forests of the southwestern US (SWUS) even in absence of stand-replacing wildfire, but regeneration in undisturbed and lightly disturbed forests has been studied infrequently and at a limited number of locations. We characterized 77 ponderosa pine sites in 7 SWUS locations, documented regeneration occurring over the past ∼20 years, and utilized gridded meteorological estimates and water balance modeling to determine the climate and environmental conditions associated with regeneration failure (R0). Of these sites, 29% were R0, illuminating that regeneration failure in these forests is widespread. R0 sites were distinguished by high above- and belowground heat loading, loss of cool-season climate, and high soil moisture variation. Explanatory variables had high accuracy in identifying R0 sites, and illustrate the climate-driven pathway by which regeneration failure has occurred in the SWUS. Regeneration failure has high potential to increase in a warmer, more hydrologically variable climate, and expand regionally from lower to higher latitudes. Yet, we also found that human management interventions were associated with environmental conditions that avoided regeneration failure. To counteract regeneration-associated forest declines, interventions will need to influence climate-driven environmental change by adjusting forest characteristics at local scales. Regeneration failures are a major threat to ponderosa pine forest persistence, and they have potential to intensify and expand in a changing climate.