Urban heat island (UHI), the phenomenon that urban areas experience higher temperatures compared to their surrounding rural areas, has significant socioeconomic and environmental impacts. With current and anticipated rapid urbanization, improved understanding of the response of UHI to urbanization is important for developing effective adaptation measures and mitigation strategies. Current studies mainly focus on a single or a few big cities and knowledge on the response of UHI to urbanization for large areas is limited. As a major indicator of urbanization, urban area size lends itself well for representation in prognostic models. However, we have little knowledge on how UHI responds to urban area size increase and its spatial and temporal variation over large areas. In this study, we investigated the relationship between surface UHI (SUHI) and urban area size in the climate and ecological context, and its spatial and temporal variations, based on a panel analysis of about 5000 urban areas of 10 km2 or larger, in the conterminous U.S. We found statistically significant positive relationship between SUHI and urban area size, and doubling the urban area size led to a SUHI increase as high as 0.7 °C. The response of SUHI to the increase of urban area size shows spatial and temporal variations, with stronger SUHI increase in Northern U.S., and during daytime and summer. Urban area size alone can explain as much as 87% of the variance of SUHI among cities studied, but with large spatial and temporal variations. Urban area size shows higher association with SUHI in regions where the thermal characteristics of land cover surrounding the urban area are more homogeneous, such as in Eastern U.S., and in the summer months. This study provides a practical approach for large-scale assessment and modeling of the impact of urbanization on SUHI, both spatially and temporally.