BACKGROUND: Excessively high and low temperatures substantially affect human health. Climate change is expected to exacerbate heat-related morbidity and mortality, presenting unprecedented challenges to public health systems. Since localised assessments of temperature-related mortality risk are essential to formulate effective public health responses and adaptation strategies, we aimed to estimate the current and future temperature-related mortality risk under four climate change scenarios across all European regions. METHODS: We modelled current and future mortality due to non-optimal temperatures across 1368 European regions, considering age-specific characteristics and local socioeconomic vulnerabilities. Overseas territories were excluded from the analysis. We applied a three-stage method to estimate temperature-related risk continuously across age and spatial dimensions. Age and city-specific exposure-response functions were obtained for a comprehensive list of 854 European cities from the Urban Audit dataset of Eurostat. Regional aggregates were calculated using an aggregation and extrapolation method that incorporates the risk incidence in neighbouring cities. Mortality was projected for present conditions observed in 1991-2020 and for four different levels of global warming (1·5°C, 2°C, 3°C, and 4°C increase) by regions, and subregions using an ensemble of 11 climate models produced by the Coordinated Regional Climate Downscaling Experiment-CMIP5 over Europe, and population projection data from EUROPOP2019. FINDINGS: Our results highlight regional disparities in temperature-related mortality across Europe. Between 1991 and 2020, the number of cold-related deaths was 2·5 times higher in eastern Europe than western Europe, and heat-related deaths were 6 times higher in southern Europe than in northern Europe. During the same time period, there were a median of 363 809 cold-related deaths (empirical 95% CI 362 493-365 310) and 43 729 heat-related deaths (39 880-45 921), with a cold-to-heat-related death ratio of 8·3:1. Under current climate policies, aligned with 3°C increase in global warming, it is estimated that temperature-related deaths could increase by 54 974 additional deaths (24 112-80 676) by 2100, driven by rising heat-related deaths and an ageing population, resulting in a cold-to-heat-related death ratio of 2·6:1. Climate change is also expected to widen disparities in regional mortality, particularly impacting southern regions of Europe as a result of a marked increase in heat-related deaths. INTERPRETATION: This study shows that regional disparities in temperature-related mortality risk in Europe are substantial and will continue to increase due to the effects of climate change and an ageing population. The data presented can assist policy makers and health authorities in mitigating increasing health inequalities by prioritising the protection of more susceptible areas and older population groups. We identify the projected areas of heightened risk (southern Europe), where policy intervention aimed at building adaptation and enhancing resilience should be prioritised. FUNDING: European Commission.