The suitability of human settlements is critical for quality of life and regional development. As comprehensive evaluations and research on the suitability of human settlements are lacking, a comprehensive evaluation of human settlements in the Yangtze River Delta (YRD) was carried out in 2020 by combining natural and human environmental elements based on multi-source data such as digital elevation models, Landsat remote sensing images, meteorological station data, and points of interest, other multi-source data, and constructions of the human settlements’ suitability indexes. The results showed the following: (1) The spatial suitability of the natural environment in the YRD is significantly affected by the topographic conditions and distance from the sea, showing an increasing spatial differentiation from southwest to northeast, with Shanghai and Yancheng having the best natural environment suitability. (2) The suitability of the human environment in urban areas is better than that in non-urban areas and shows a decreasing trend from the south to the north circle. Shanghai, Zhoushan, and Huaibei have the best human environment suitability. (3) The comprehensive suitability of human settlements includes both the spatial differentiation characteristics of the suitability of natural and human environments. Shanghai and Zhoushan have the mosy comprehensive suitability for human settlements, while Huaibei and Xuzhou have the worst. (4) Land with a comprehensive suitability for human settlements of greater than 0.580 accounts for 23.60% of the total and contains 30.08% of the population and 32.31% of the economy, indicating that areas with a high suitability index have been fully utilized, and the populations and economies with human settlements suitability have a high degree of matching.