The host immune response against severe acute respiratory syndrome coronavirus 2 includes the induction of a group of natural antiviral cytokines called interferons (IFNs). Although originally recognized for their ability to potently counteract infections, the mechanistic functions of IFNs in patients with varying severities of coronavirus disease 2019 (COVID-19) have highlighted a more complex scenario. Cellular and molecular analyses have revealed that timing, location, and subtypes of IFNs produced during severe acute respiratory syndrome coronavirus 2 infection play a major role in determining disease progression and severity. In this review, we summarize what the COVID-19 pandemic has taught us about the protective and detrimental roles of IFNs during the inflammatory response elicited against a new respiratory virus across different ages and its longitudinal consequences in driving the development of long COVID-19.