The unique marine and terrestrial ecosystems of the Galapagos Islands are highly vulnerable to human-based drivers of change, including the introduction of invasive species, unsustainable tourism, illegal fishing, overexploitation of ecosystem services, and climate change. These drivers can interact with climate-based drivers such as El Niño-Southern Oscillation (ENSO) at multiple temporal and spatial scales, exacerbating their negative impacts on already fragile ecosystems and the socioeconomic system of the Archipelago. In this review, we performed a literature review based on published literature from 1945 to 2020 and local and global climate databases to analyze drivers of change in the Galapagos. We developed and applied a spatial impact assessment model to identify high-ecological value areas with high sensitivity and exposure scores to environmental change drivers. We identified 13 priority HEVA that encompass ca. 23% (14,715 km2) of the Galapagos Archipelago, distributed in nearly 3% of the Galapagos Marine Reserve and 20% Galapagos National Park. Current and future impacts are likely to concentrate on the inhabited islands’ highlands, whereas marine impacts concentrate along most of the Galapagos Islands’ shorelines. These results are important for guiding the design and implementation of adaptation measures aimed at increasing ecosystem resilience and human adaptive capacity in the face of global environmental change. Overall, these results will be valuable in their application for preserving Galapagos biota, securing the provision of vital ecosystem services for resident human populations, and sustaining the nature-based tourism industry.