Excess nitrogen and phosphorus inputs are the main causes of aquatic environmental deterioration. Accurately quantifying and dynamically assessing the regional nitrogen and phosphorus pollution emission (NPPE) loads and influencing factors is crucial for local authorities to implement and formulate refined pollution reduction management strategies. In this study, we constructed a methodological framework for evaluating the spatio-temporal evolution mechanism and dynamic simulation of NPPE. We investigated the spatio-temporal evolution mechanism and influencing factors of NPPE in the Yangtze River Economic Belt (YREB) of China through the pollution load accounting model, spatial correlation analysis model, geographical detector model, back propagation neural network model, and trend analysis model. The results show that the NPPE inputs in the YREB exhibit a general trend of first rising and then falling, with uneven development among various cities in each province. Nonpoint sources are the largest source of land-based NPPE. Overall, positive spatial clustering of NPPE is observed in the cities of the YREB, and there is a certain enhancement in clustering. The GDP of the primary industry and cultivated area are important human activity factors affecting the spatial distribution of NPPE, with economic factors exerting the greatest influence on the NPPE. In the future, the change in NPPE in the YREB at the provincial level is slight, while the nitrogen pollution emissions at the municipal level will develop towards a polarization trend. Most cities in the middle and lower reaches of the YREB in 2035 will exhibit medium to high emissions. This study provides a scientific basis for the control of regional NPPE, and it is necessary to strengthen cooperation and coordination among cities in the future, jointly improve the nitrogen and phosphorus pollution tracing and control management system, and achieve regional sustainable development.