Dairy farming is one the most important sectors of United Kingdom (UK) agriculture. It faces major challenges due to climate change, which will have direct impacts on dairy cows as a result of heat stress. In the absence of adaptations, this could potentially lead to considerable milk loss. Using an 11-member climate projection ensemble, as well as an ensemble of 18 milk loss estimation methods, temporal changes in milk production of UK dairy cows were estimated for the 21st century at a 25 km resolution in a spatially-explicit way. While increases in UK temperatures are projected to lead to relatively low average annual milk losses, even for southern UK regions (<180 kg/cow), the ‘hottest’ 25×25 km grid cell in the hottest year in the 2090s, showed an annual milk loss exceeding 1300 kg/cow. This figure represents approximately 17% of the potential milk production of today’s average cow. Despite the potential considerable inter-annual variability of annual milk loss, as well as the large differences between the climate projections, the variety of calculation methods is likely to introduce even greater uncertainty into milk loss estimations. To address this issue, a novel, more biologically-appropriate mechanism of estimating milk loss is proposed that provides more realistic future projections. We conclude that South West England is the region most vulnerable to climate change economically, because it is characterised by a high dairy herd density and therefore potentially high heat stress-related milk loss. In the absence of mitigation measures, estimated heat stress-related annual income loss for this region by the end of this century may reach £13.4M in average years and £33.8M in extreme years.