Climate change is creating an increase in temperatures, which is harming the quality of life of people all over the world, particularly those with minimal financial resources. While 30% of the world’s population is now vulnerable to extreme heat, estimates show that ratio will rise to 74% in the next 20 years, according to forecasts. Using the UrbClim climate model, this study examines the space-time variability of the heat stress index (HI) in different local climate zones (LCZs), as well as how heat wave conditions might affect this index based on land use and land cover. To that end, Seville, in Southern Spain, was investigated during the summer of 2017, when it had four heat waves. The following indices were considered for each urban sub-area: Normalized Difference Vegetation, Proportion Vegetation, Normalized Difference Built, and Urban Index. The goal is to conduct a statistical analysis of the link between the aforementioned elements and the heat stress index in order to recommend mitigation and resilience techniques. Our findings showed that compact and industrial LCZs (2, 3, and 10) are less resistant to HI than open and rural regions (5, 6, B, D, and G), which are more resistant to HI due to higher vegetation rates. The heat wave condition exacerbates the HI in all LCZs. As a result, initiatives such as enhancing open space, increasing green space, or using green roofs and façades might alleviate heat stress and improve people’s quality of life.