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Urban green infrastructure, especially trees, are widely regarded as one of the most effective ways to reduce urban temperatures in heatwaves and alleviate the adverse impacts of extreme heat events on human health and well-being. Nevertheless, urban planners and decision-makers are still lacking methods and tools to spatially evaluate the cooling effects of urban green spaces and exploit them to assess greening strategies at the urban agglomeration scale. This article introduces a novel spatially explicit approach to simulate urban greening scenarios by increasing the tree canopy cover in the existing urban fabric and evaluating their heat mitigation potential. The latter is achieved by applying the InVEST urban cooling model to the synthetic land use/land cover maps generated for the greening scenarios. A case study in the urban agglomeration of Lausanne, Switzerland, illustrates the development of tree canopy scenarios following distinct spatial distribution strategies. The spatial pattern of the tree canopy strongly influences the human exposure to the highest temperatures, and small increases in the abundance of tree canopy cover with the appropriate spatial configuration can have major impacts on human health and well-being. The proposed approach supports urban planning and the design of nature-based solutions to enhance climate resilience.