Transitions to terrestrial ecosystems attributable to land cover and land use change (LCLUC) and climate change can affect the climate at local to regional scales. However, conclusions from most previous studies do not provide information about local climate effects, and little research has directly quantified how LCLUC intensity within different ecoregions relates to climate variation. In this study, we present an observation-based analysis of climate sensitivity to LCLUC based on decadal LCLUC and climate data in different ecoregions. Our results revealed that variations in land surface temperature and vapor pressure were most sensitive to LCLUC across the conterminous United States, while precipitation was less sensitive. Persistent warming effects were produced from LCLUC in Appalachian and some of the central U.S., High Plains, and northwest ecoregions, but cooling effects were evident in the many southeast, northeast and some Great Lakes and Intermountain West ecoregions. Most of the warming and a few cooling ecoregions were sensitive to LCLUC. Ecoregions with increasing vapor pressure were found across the Great Plains, Intermountain West, and West Coast ecoregions and several of these regions in the Great Plains and West Coast were sensitive to LCLUC. A combination of changes in temperature, precipitation, and vapor pressure was used to characterize climate sensitivity associated with LCLUC forcing, and five major persistent patterns were found in some ecoregions. These findings suggest that climate conditions, especially temperature and vapor pressure, in some ecoregions are sensitive to LCLUC and such change should be better incorporated into regional climate assessments.