Abstract: Technological innovation is the strategic support for improving social productivity and comprehensive national strength. Only by accurately grasping the regional differences in the scientific and technological innovation efficiency and their causes can the scientific and technological innovation efficiency be improved in a targeted and precise manner. In the framework of data envelopment analysis, this paper constructs a super-efficiency EBM model to evaluate the scientific and technological innovation efficiency of China’s major national strategic regions, uses the Theil index method to reveal the regional differences in the scientific and technological innovation efficiency, and uses the QAP method to identify the causes of regional differences. The results show that the scientific and technological innovation efficiency in China's major national strategic regions is on the rise during the sample period. In particular, since the 18th National Congress of the Communist Party of China, the scientific and technological innovation efficiency in major national strategic regions has improved rapidly. On the whole, the regional differences show a downward trend. The intra-regional differences are the main source of the overall regional differences, and the regional differences of technology market turnover are the decisive force of the regional differences of scientific and technological innovation efficiency in major national strategic regions. To implement innovation-driven development strategy and regional coordinated development strategy in the new era, it is necessary to correctly understand the current situation and regional differences of the scientific and technological innovation efficiency in major national strategic regions, which is of great significance for comprehensively coordinating the improvement of the scientific and technological innovation efficiency in China.