As the climate warms, increasing heat-related health risks are expected, and can be exacerbated by the urban heat island (UHI) effect. UHIs can also offer protection against cold weather, but a clear quantification of their impacts on human health across diverse cities and seasons is still being explored. Here we provide a 500 m resolution assessment of mortality risks associated with UHIs for 85 European cities in 2015-2017. Acute impacts are found during heat extremes, with a 45% median increase in mortality risk associated with UHI, compared to a 7% decrease during cold extremes. However, protracted cold seasons result in greater integrated protective effects. On average, UHI-induced heat-/cold-related mortality is associated with economic impacts of €192/€ − 314 per adult urban inhabitant per year in Europe, comparable to air pollution and transit costs. These findings urge strategies aimed at designing healthier cities to consider the seasonality of UHI impacts, and to account for social costs, their controlling factors, and intra-urban variability.