COVID-19 has governments at all levels operating in a context of radical uncertainty. The regional and local impact of the COVID-19 crisis is highly heterogeneous, with significant implications for crisis management and policy responses. This paper takes an in-depth look at the territorial impact of the COVID-19 crisis in its different dimensions: health, economic, social and fiscal. It provides examples of responses by national and subnational governments to help mitigate the territorial effects of the crisis, and offers ten takeaways on managing COVID-19’s territorial impact. Finally, the paper offers a forward looking perspective to discuss the crisis’ implications for multi-level governance as well as points for policy-makers to consider as they build more resilient regions.