With the recent changes in population structure and continuous urbanization, the degree of population shrinkage in mountain cities has increased, especially under the impact of the COVID-19 epidemic, and the economic development of such mountain cities has become a prominent issue. The epidemic has not only exposed the vulnerability of these cities to economic development but also aggravated the negative impact of population contraction, bringing about new challenges and pressures related to regional population development and economic resilience. This change has become an important topic in the study of mountain cities. Therefore, taking Guizhou Province as a case study, this work applies the population change rate, the entropy method, and a mediation effect model to study the spatiotemporal evolution of population shrinkage and economic resilience, and it explores how population shrinkage influences economic resilience. The results reveal the following: (1) Few counties experienced population shrinkage in Guizhou Province from 2013 to 2017, indicating a sporadic distribution pattern, whereas the degree of population shrinkage increased rapidly from 2018 to 2022, revealing an east–west symmetrical distribution pattern, with Guiyang city located on the central axis. (2) There are significant regional differences in the spatial distribution of the level of economic resilience between the two periods. Under the impact of COVID-19, from 2019 to 2022, although the overall level of economic resilience increased, the level of resilience in most counties tended to decrease. (3) Regarding the mediating effect, population shrinkage affected the level of economic resilience through general public budget expenditure, foreign trade investment, new urban employment, and GDP. The abovementioned findings are helpful for providing theoretical support and empirical guidance for the sustainable development of mountain cities in the face of population contraction, economic challenges, and promoting regional coordination.