The extent to which climate change and other factors will influence building energy use and population exposures to indoor pollutants is not well understood. Here, we develop and apply nationally representative residential energy and indoor pollutant model sets to estimate energy use, indoor pollutant concentrations, and associated chronic health outcomes across the U.S. residential building stock in the mid-21st century. The models incorporate expected changes in meteorological and ambient air quality conditions associated with IPCC RCP 8.5 and assumptions for changes in housing characteristics and population movements while keeping other less predictable factors constant. Site and source energy consumption for residential space-conditioning are predicted to decrease by ∼37-43 and ∼20-31%, respectively, in the 2050s compared to those in a 2010s reference scenario. Population-average indoor concentrations of pollutants of ambient origin are expected to decrease, except for O(3). Holding indoor emission factors constant, indoor concentrations of pollutants with intermittent indoor sources are expected to decrease by <5% (PM(2.5)) to >30% (NO(2)); indoor concentrations of pollutants with persistent indoor sources (e.g., volatile organic compounds (VOCs)) are predicted to increase by ∼15-45%. We estimate negligible changes in disability-adjusted life-years (DALYs) lost associated with residential indoor pollutant exposures, well within uncertainty, although the attribution among pollutants is predicted to vary.