The COVID-19 pandemic has caused an abrupt break in economic, demographic and social dynamics, both in developing countries and advanced economies, perhaps with a more significant impact in the latter, though further evidence is needed to support this assumption. Unfortunately, earlier research on medium- and long-term impacts of the pandemic on urban and regional systems—with particular reference to the demographic dimension—have not yet reached a consensus on methodological and operational approaches. In the present study, we have applied an interpretative framework to the analysis of the demographic balance in Italy, one of the most affected countries in the world, before and during the COVID-19 pandemic. Specifically, we have compared a wide set of demographic indicators at two time periods of equal duration (2002–2010 and 2011–2019) and in two subsequent years (2020 and 2021), controlling for the regional context. These periods were chosen as sufficiently long to be representative of differentiated economic dynamics (2002–2010: economic expansion and demographic recovery; 2011–2019: recession and consequent demographic decline). Years 2020 and 2021 were assumed to reflect the short- and medium-term impact of the COVID-19 pandemic. The results of the statistical analysis highlight how the COVID-19 pandemic has exerted considerable pressure on population dynamics, determining short-term (mortality increase), medium-term (more volatile migration flows) and long-term (fertility decline) effects. Future studies should clarify the aggregate role of pandemics in population dynamics as a possible proxy of the decline of demographically fragile regions in advanced economies.