Entrepreneurship plays a key role in transforming the economy and society by stimulating economic development, testing innovative ideas, creating new jobs, and by enriching the quality of life and human existence. Entrepreneurship dynamics depend upon a series of local and national economic factors, but are also affected by the international environment, such as the current COVID-19 pandemic. Statistical data show that new businesses are created at a slower rate during an economic crisis, when the economic climate is harsh, and business opportunities are scarce. Nevertheless, there are local differences in the reaction to crises, and new business formation tends to decline with variable intensity from one region to another, even in the same country. The crises are acting as a trigger for some opportunity-driven entrepreneurs, and resilient regions can thrive even in times of crisis or recover faster after a depression. To capture spatial interactions, as well as spatial short- and long-term effects, the method employed in our analysis relies on the estimation of dynamic spatial panel models. We tested the potential impact of a large variety of social and economic indicators on the creation of new firms and found that the most consequential factors of influence are the economic crisis (expressed through a binary variable), GDP per capita, FDI per capita, inflation, unemployment, and education. Our results convey a powerful policy message for both national and regional decision makers. We believe that, while putting entrepreneurial initiative to the test, the current COVID-19 crisis might act as a catalyst that leads to innovation and reshapes the economy and society.