Abstract: The rapid development of high-speed rail has significantly improved intercity accessibility and connectivity, which has influenced spatial resource reallocations and changed regional economic development patterns. Taking 40 prefecture-level or above cities in the Yangtze River Delta (YRD) region as a case study, this paper employs urban strength index and intercity connection strength and compares the values before and after the operation of high-speed railway (2009 and 2018) to reveal the accessibility and connectivity changes in the YRD. It further analyzes the influences on economic development over the past decade by use of an improved production function model. The results show that: (1) The rapid high-speed rail development reduced the average shortest time accessibility of cities in the YRD by 0.257 h per year, and nearly doubled the network connectivity in the past decade, leading to much higher intercity accessibility and connectivity. (2) There were obvious regional differences across cities in the improvement of urban strength index and intercity connection strength in the past decade. The spatial accessibility for cities located in the peripheral YRD had higher increase, while the spatial connectivity for cities with higher level of development had the higher improvement. Central cities functioned as transport hubs had been enhanced from the development of HSR network, which created a significant Matthew effect of accumulated advantage. (3) The pattern of urban strength index was uneven distributed and the disparity had been increased significantly, which was mainly resulted from some transport hub cities’ much higher increase in urban strength values. (4) The evolution of high-speed rail network significantly influenced regional economic development pattern, particularly the tertiary industries, which led to a more polarized distribution of economic development in the YRD. This study offers some evidence to support high-speed rail-oriented development, regional planning and regional economic integration policies-making in the context of high-speed rail expansion in regional China.