The development of urban accumulations in recent decades has led to the transformation of urban heat islands (UHI) into regional heat islands (RHI). The contributions of the biophysical, climate, and socioeconomic factors to RHI in urban agglomeration remain poorly understood. Here Yangtze River Delta urban agglomeration (YRDUA) in eastern China has been selected as a case area to explore the influences trends, of the influencing factors to RHI by using MODIS data from 2003 to 2017. Results showed that, in summer, the area fraction of daytime RHI in YRDUA has increased from 21.74 to 31.03% in 2003 and 2017, respectively. As compared to 2003, the annual nighttime RHI area in 2017 has increased from 7510 to 20,097 km2. The dominant factors of surface RHI intensity (SRHII) showed seasonal variation. Enhanced vegetation index (EVI) (interpretation of 33.27%) was the dominant factor of daytime SRHII in spring. The most important factor was normalized difference build-up density (NDBI) (37.28% and 26.83%, respectively) in summer and autumn. In winter, precipitation (26.16%) was the most influential. At night, Modified Normalized Difference Water Index (MNDWI) had a dominant effect on SRHII in spring (54.12%), autumn (52.62%), and winter (24.19%). The dominant factor of nighttime SRHII in summer was EVI (42%). Moreover, water bodies harm RHI during the day while having a positive effect at night. These findings can provide a theoretical basis for regional environment improvement and regional sustainable development.