Sustainable innovation is a new paradigm for innovative development related to sustainable development. This paper selects 41 cities in the Yangtze River Delta region from 2012 to 2021. It applies the super-efficiency SBM-Undesirable model to measure regional sustainable innovation efficiency (RSIE). It introduces the standard deviation ellipse, the Hurst index, spatial econometric models, etc., to depict the spatial pattern, spatiotemporal evolution, and the driving forces of the RSIE. The results show that: 1) The RSIE in the study region showed a basic trend of fluctuation and increase during the study period, with regional differences decreasing year by year. 2) The RSIE is distributed in a “southeast-northwest” direction, and the center of gravity is shifted in a spatial characteristic of “first to the south, then to the north”. 3) Nanjing, Hangzhou, and their surrounding areas will emerge as the future growth poles for the RSIE. 4) A favorable socio-cultural and innovative learning environment, high salary levels, and enterprise clustering boost the RSIE, while unreasonable government funding and environmental regulation hinder it. Both government funding and enterprise clustering exhibit positive spatial spillovers, while infrastructure has negative ones.