Sustainable development is central to the current societal functioning, whose complexity demands consideration on a regional scale. However, there are disparate methods to express sustainable development, many of which use qualitative analysis cumbersome for policy-makers. Previous studies focused on environmental, economic, and social impacts without fully considering the regulation mechanisms of the plethora of administrative bodies. To fill this research gap, this research establishes an integrated assessment framework involving four pillars: environment and ecology, society and culture, economics, and governance and policy. Further, indicator systems and quantitative analysis give comparable and objective results. The current study applied them to one of the most economically significant and developed Chinese regions, the Yangtze River Delta. The result shows a dynamic variation in regional sustainability from 2010 to 2019, indicating an annual increase. Although economic and societal development has been increasing steadily, environmental development has stagnated in the past two years, and the influencing policy has fluctuated dramatically. Our analysis was done in Shanghai, Jiangsu, Zhejiang, and Anhui. Even though all regions showed increasing sustainability, we observed an imbalance in regional sustainable development. Achieving a regional approach and enhanced regional coordination in the Yangtze River Delta is imperative and cannot be ignored by local, regional, and national policy-makers. More importantly, this study created a model capable of predicting the impact of the COVID-19 epidemic on regional sustainable development. The model showed that, compared with predicted values, a 6.65% decrease in the integrated sustainability index ensued, attributed to the pandemic in Zhejiang province.