This paper focuses on the total factor productivity (TFP) and high-quality economic development in China by examining 11 Chinese provinces and cities in the Yangtze River Economic Belt from 2007 to 2018. We use the Solow residual method to calculate the TFP growth rate of the 11 provinces and cities. Based on the panel data, we have analyzed the influencing factors of TFP theoretically and empirically from the overall region and upstream region, and midstream region and downstream region, respectively. The regression results show that: (1) The whole characteristics generally show the TFP growth trend of the upstream region, midstream region and downstream region are consistent with that of the overall region, and the growth rate of TFP slows down gradually. Meanwhile the differences in TFP growth between the upstream region, midstream region and downstream region show an increase at first and then a decrease. (2) Regarding the influencing factors, there are differences in the direction and extent of the impact of each factor such as the level of openness, R&D investment, industrial structure, government expenditure and human capital on the TFP of the overall region, upstream region, midstream region and downstream region. (3) Based on the results of the theoretical and empirical analysis, we have proposed a series of measures for the sustainable high-quality development of the Yangtze River Economic Belt.