Based on the data of 22 different countries from 2005 to 2018, this paper mainly studies the influence of entrepreneurship on sustainability, and further explores the influence of Economic Policy Uncertainty (EPU) and the interaction effect between EPU and entrepreneurship on sustainability. The results show that EPU can promote economic, environmental, and social development, the interaction between EPU and green entrepreneurship is beneficial to social development, and the interaction between EPU and non-green entrepreneurship inhibits social development. For the heterogeneity analysis, 22 countries are grouped by high and low Human Development Index (HDI). The empirical results find that EPU has a better performance in low HDI countries than that in high HDI countries. In high HDI countries, the interaction between EPU and green entrepreneurship will weaken the positive effects of green entrepreneurship on the environment.