Under economic fluctuations, the sustainable development of enterprises is crucial. Currently, there are few studies on the interaction between economic policy uncertainty (EPU) and the sustainable development behavior of enterprises. Based on a panel vector autoregressive (PVAR) model, this paper explores the static and dynamic interactions among EPU, enterprise investment, and enterprise profitability and then analyzes regional heterogeneity in these factors. It finds that EPU has an inhibitory effect on the investment and profitability of enterprises, while the investment and profitability of enterprises also have an inhibitory effect on EPU. In addition, there are contribution differences and regional differences in the degrees of influence of the three factors. In the long run, EPU and the inhibition of enterprise investment and profitability are strongest in China’s central region. The results show that the stronger the certainty of economic policy, the more conducive this policy is to promoting enterprise investment behavior and improving enterprise profitability. Therefore, to ensure normal economic development, the government should limit changes in economic policy as much as possible; doing so is critical for promoting investment behavior and improving the profitability of enterprises.