High-speed rail has strong impact on the spatial pattern of regional economy in the Pearl River Delta urban agglomeration. Exploring the coupling of high-speed rail and regional economy is thus of great scientific value. In this paper, we comprehensively quantified the impact of high-speed rail on the spatial pattern of regional economy over the Pearl River Delta urban agglomeration using cities panel data in 2010, 2014, and 2018. We quantified the regional economic connection, regional advantage potential, and regional economic space stability, respectively, using gravity model, regional superiority potential model, and Theil coefficient. Our results show that: (1) the intensity of economic relations between cities in the Pearl River Delta increased over years, with a stronger economic relations along north-south direction than the east-west direction. Core zones of economic relations included Guangzhou, Shenzhen, Dongguan, and Foshan.The sub-zones of economic relations were represented by Zhongshan, Zhaoqing, and Huizhou. And the radiated zones of economic relations covered the whole Pearl River Delta. The regional influence of high-speed rail on the economic development of the Pearl River Delta cities was also uneven. Guangzhou, Shenzhen, Dongguan, Foshan, and other cities with strong economic strength occupied the core positions. As a result, the economic ties between other cities may need to be improved in the future; (2) with the construction and operation of high-speed rail, the regional advantage of each city over surrounding cities increased greatly from 2010 to 2018. However, the differences in regional advantages of each cityalso increased gradually. Dongguan, Zhongshan and other second- and third-tier cities with strong economic strength, small urban geographical scale, small population scale, and superior geographical location benefited most. These cities had great potential to be new regional growth centers in future; (3) for the overall difference of regional economy in the Pearl River Delta, the spatial heterogeneity of regional economy increased first and then decreased. For the group differences in the area, the difference of economic development levels between first-and second-tier cities showed a significant increase first and a slight decrease trend then. The difference of economic development levels between second-and third-tier cities showed a decreasing trend. The study provide useful references for future transportation planning.