The Middle East and North Africa (MENA) is one of the regions that is most vulnerable to the negative effects of climate change, yet the potential public health impacts have been underexplored compared to other regions. We aimed to examine one aspect of these impacts, heat-related mortality, by quantifying the current and future burden in the MENA region and identifying the most vulnerable countries. We did a health impact assessment using an ensemble of bias-adjusted statistically downscaled Coupled Model Intercomparison Project phase 6 (CMIP6) data based on four Shared Socioeconomic Pathway (SSP) scenarios (SSP1-2·6 [consistent with a 2°C global warming scenario], SSP2-4·5 [medium pathway scenario], SSP3-7·0 [pessimistic scenario], and SSP5-8·5 [high emissions scenario]) and Bayesian inference methods. Assessments were based on apparent temperature-mortality relationships specific to each climate subregion of MENA based on Koppen-Geiger climate type classification, and unique thresholds were characterised for each 50 km grid cell in the region. Future annual heat-related mortality was estimated for the period 2021-2100. Estimates were also presented with population held constant to quantify the contribution of projected demographic changes to the future heat-mortality burden. The average annual heat-related death rate across all MENA countries is currently 2·1 per 100 000 people. Under the two high emissions scenarios (SSP3-7·0 and SSP5-8·5), most of the MENA region will have experienced substantial warming by the 2060s. Annual heat-related deaths of 123·4 per 100 000 people are projected for MENA by 2100 under a high emissions scenario (SSP5-8·5), although this rate would be reduced by more than 80% (to 20·3 heat-related deaths per 100 000 people per year) if global warming could be limited to 2°C (ie, under the SSP1-2·6 scenario). Large increases are also expected by 2100 under the SSP3-7·0 scenario (89·8 heat-related deaths per 100 000 people per year) due to the high population growth projected under this pathway. Projections in MENA are far higher than previously observed in other regions, with Iran expected to be the most vulnerable country. Stronger climate change mitigation and adaptation policies are needed to avoid these heat-related mortality impacts. Since much of this increase will be driven by population changes, demographic policies and healthy ageing will also be key to successful adaptation. National Institute for Health Research, EU Horizon 2020.