Sagebrush ecosystems across the western U.S. are in decline due to numerous threats, including expansion of coniferous woodlands and forests. The interagency Sagebrush Conservation Design effort recently quantified sagebrush ecological integrity (SEI) to map remaining core sagebrush areas (relatively intact and functional sagebrush ecosystems) and understand spatial and temporal patterns of change relative to primary threats. Recent work has identified conifer expansion as the second leading cause of decline in sagebrush ecological integrity biome wide. Here, we sought to create a spatial prioritization of conifer management that maximizes return-on-investment to defend and grow core sagebrush areas. Multi-criteria decision analysis (MCDA) was used to incorporate a series of biome-level inputs including SEI, invasive annual grass cover and risk, structural connectivity, and conifer cover and expansion vulnerability into a single prioritization based on collaborative expert input. Our analysis identifies priority areas for conifer management across the sagebrush biome, simulates conifer treatments based on those priorities, and estimates potential changes in SEI as a result of targeted treatment. At a broad scale, we found that the highest priority areas for conifer management were largely located east of the Rocky Mountains. This represents a departure from recent landscape-level trends of conifer management efforts in sagebrush systems, which were focused primarily on pinyon-juniper expansion in the Great Basin. A majority (52%) of the highest priority areas are managed by the Bureau of Land Management, followed by a large proportion (26%) of priority areas located on privately-owned land – particularly in Wyoming and Montana. Targeting simulated conifer treatments using our prioritization resulted in higher within-core targeting percentages (≥93%) than business-as-usual efforts (23.8%), which would result in a four-to eight-fold reduction in the time to treat priority areas within cores. Finally, we demonstrate that these simulated treatments, targeted with our prioritization, have the capacity to improve SEI in and around treatment areas. This work provides an actionable path to “Defend the Core” as outlined by the Sagebrush Conservation Design effort by helping conservationists more efficiently address conifer expansion in and around core sagebrush areas.