Extreme climatic events, environmental degradation and socio-economic inequalities exacerbate the risk of infectious disease epidemics. We lack the evidence-base to understand and predict the impacts of extreme events and landscape changes on disease risk, leaving communities in climate change hotspots vulnerable to increasing health threats. This is in part due to a lack of ‘ground truth’ data describing environmental change in remote and under-resourced areas, as well as a lack of trained research software engineers and data scientists. HARMONIZE will convene a transdisciplinary community of stakeholders, software engineers and data scientists to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots, including cities, small islands, highlands and the Amazon rainforest. We will strategically undertake one-off longitudinal ground truth data collection using drone technology and low-cost weather sensors, to improve classification algorithms and downscaling of coarser-resolution environmental datasets (e.g., satellite images, climate reanalysis and forecasts). We will then harmonize this post-processed data with socio- economic and health data in an automated workflow packaged for users in bespoke hotspot-specific toolkits. These sustainable tools will facilitate generation of actionable knowledge to inform local risk mapping and build robust early warning and response systems to build resilience in low-resource settings.