According to the new development pattern, implementing the development strategy driven by scientific and technological innovation (STI) is an important measure for each region to improve the quality of regional economic development. Exploring the effect of STI on the regional high-quality economic development (HED) is helpful to break the bottleneck and enhance the momentum of regional economic development. The Yangtze River Delta, located in the east coast of China, is the frontier of STI and economic development. Based on theoretical analysis, this paper uses the entropy method to calculate the STI index of the Yangtze River Delta from 2009 to 2018, and systematically investigates the impact of STI on HED in Yangtze River Delta by using two-way fixed effect, spatial Dubin model, panel threshold model and moderation effect model. The research finds that: First, under the control of other factors, STI has significantly promoted the HED of Yangtze River Delta region, while it also produces a spatial spillover effect. Second, the impact of STI on HED in the Yangtze River Delta has a double threshold effect based on the advanced industrial structure. Third, the analysis of adjustment mechanism shows that the scale of higher education has a positive adjustment effect in the relationship between STI and HED. Fourth, with the further analysis of regional heterogeneity, the economic effect of STI in central cities is significantly greater than that in noncentral cities. These findings provide theory-based direction and policy inspiration for improving the institutional mechanism of STI and accelerating the promotion of HED in Yangtze River Delta region.