Protected areas are critical for conserving California’s many sensitive plant species but their future role is uncertain under climate change. Climate-driven species losses and redistributions could dramatically affect the relevance of protected areas for biodiversity conservation this century. Focusing on the University of California Natural Reserve System (NRS), we predicted the future impact of climate change on reserve effectiveness with respect to sensitive plant protection. First, we evaluated the historical representation of sensitive plant species in the NRS reserve network by compiling species accounts from checklists, floras, and spatial queries of occurrence databases. Next, we calculated projected climate change exposure across the NRS reserve network for the end of the 21st century (2070–2099) relative to baseline (1971–2000) conditions under five future climate scenarios. We then predicted statewide changes in suitable habitat for 180 sensitive plant taxa using the same future climate scenarios in a species distribution modeling approach. Finally, from these predictions we evaluated suitable habitat retention at three spatial scales: individual NRS reserves (focal reserves), the NRS reserve network, and the surrounding mosaic of protected open space. Six reserves—Sagehen Creek Field Station, McLaughlin Natural Reserve, Jepson Prairie Reserve, Landels-Hill Big Creek Reserve, Sedgwick Reserve, and Boyd Deep Canyon Desert Research Center—were selected as focal reserves for analyses.