High-speed railway has made a deep impact on the regional economy for developed countries. In recent years, high-speed rail has brought great effect on stimulating China’s economic and social development. The current research on high-speed rail mostly exists in theory, and lack of quantitative research using the precise algorithm to study the effect of high-speed railway on regional economy. This paper firstly analyzes the influence mechanism of high-speed rail. In addition, quantitative analysis in this paper, it uses the panel data model to calculate the economic influence of high-speed rail by taking the Wuhan-Guangzhou high-speed railway as an example, and adopting comparative analysis to analysis the influence on regional economic development before and after the operation of Wuhan-Guangzhou high-speed railway. The result shows that high-speed railway effects regional economy though economic growth, industrial structure and cities’ spatial structure optimization and improvement of regional cooperation. Besides, economic effects of high-speed railway are different in regions with different scales and develop stages, which may increase the gaps between big cities and small cities.