Climate change is anticipated to increase the frequency and intensity of droughts, with major impacts to ecosystems globally. Broad-scale assessments of vegetation responses to drought are needed to anticipate, manage, and potentially mitigate climate-change effects on ecosystems. We quantified the drought sensitivity of vegetation in the Pacific Northwest, USA, as the percent reduction in vegetation greenness under droughts relative to baseline moisture conditions. At a regional scale, shrub-steppe ecosystems—with drier climates and lower biomass—showed greater drought sensitivity than conifer forests. However, variability in drought sensitivity was considerable within biomes and within ecosystems and was mediated by landscape topography, climate, and soil characteristics. Drought sensitivity was generally greater in areas with higher elevation, drier climate, and greater soil bulk density. Ecosystems with high drought sensitivity included dry forests along ecotones to shrublands, Rocky Mountain subalpine forests, and cold upland sagebrush communities. In forests, valley bottoms and areas with low soil bulk density and high soil available water capacity showed reduced drought sensitivity, suggesting their potential as drought refugia. These regional-scale drought-sensitivity patterns discerned from remote sensing can complement plot-scale studies of plant physiological responses to drought to help inform climate-adaptation planning as drought conditions intensify.