<p>Understanding the dynamic relationships among multidimensional human wellbeing (MHW) is crucial for advancing the 2030 Sustainable Development Goals and fostering regional sustainability. In this study, we quantified and mapped economic wellbeing (ECOW), social wellbeing (SOCW), and environmental wellbeing (ENVW) in the Yangtze River Delta Urban Agglomeration (YRDUA) from 2001 to 2021 using multi-source panel data. We then investigated the spatio-temporal synergies/trade-offs and driving forces of MHW through multi-scale geospatial analysis and machine learning methods. The results represent: (1) High-value areas of ECOW and SOCW were similarly concentrated in developed eastern cities, while northern Zhejiang and southern Anhui’s forest regions exhibited the highest ENVW. (2) The temporal correlation and most cities’ spatial correlation among MHW were positive, indicating a macro trend of synergistic growth. The correlation intensity of ECOW-SOCW was significantly higher than that of ECOW-ENVW and SOCW-ENVW. (3) From a micro perspective, nearly all cities had encountered varying degrees of MHW trade-offs at different time points. The alternating patterns of synergies and trade-offs embodied the wave-like progression toward regional sustainability. Developed and underdeveloped cities had relatively higher synergy indices in ECOW-SOCW and SOCW-ENVW, respectively, while medium-developed cities demonstrated the strongest trade-offs in ECOW-ENVW. (4) The dominant factors for ECOW, SOCW, and ENVW showed some differences, with industrial structure, economic development, government intervention, employment situation, population size, and terrain features serving as core forces. The positive influence of most factors drove the emergence of synergistic trend, while frequent trade-offs observed at finer scales mainly stemmed from fluctuations in non-linear effects.</p>