This study measured the economic resilience of 269 prefecture-level cities in China by constructing an indicator evaluation system for the resilience, adjustment, and responsiveness of the economic system under external shocks. A dynamic spatial Durbin model and a moderating mediation model were employed to analyze empirically the impact of economic policy uncertainty and innovative entrepreneurial vitality on economic resilience using prefecture-level panel data from 2004 to 2018. The statistical results revealed that there were significant “snowball” effects and spatial spillover characteristics of economic resilience. Under the moderating effect of economic policy uncertainty, innovative entrepreneurial vitality was found to have a significant positive effect on economic resilience. Furthermore, innovative entrepreneurial vitality was found to enhance economic resilience significantly by upgrading the industrial structure, alleviating the income gap, and guiding economic agglomeration in the context of economic policy uncertainty. Moreover, the impacts of innovative entrepreneurial vitality and economic policy uncertainty on economic resilience, respectively, showed significant heterogeneities in terms of the cities’ regions and economic sizes. The above-mentioned results were found to be valid even after a series of robustness tests were carried out.