Abstract The coronavirus disease (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, is leading to unknown and unusual health conditions that are challenging to manage. Post-COVID-19 syndrome is one of those challenges, having become increasingly common as the pandemic evolves. The latest estimates suggest that 10 to 20% of the SARS-CoV-2 patients who undergo an acute symptomatic phase are experiencing effects of the disease beyond 12 weeks after diagnosis. Although research is beginning to examine this new condition, there are still serious concerns about the diagnostic identification, which limits the best therapeutic approach. Exercise programs and physical activity levels are well-known modulators of the clinical manifestations and prognosis in many chronic diseases. This narrative review summarizes the up-to-date evidence on post-COVID-19 syndrome to contribute to a better knowledge of the disease and explains how regular exercise may improve many of these symptoms and could reduce the long-term effects of COVID-19. Open access, https://www.mdpi.com/1660-4601/18/10/5329/htm "Currently, there is no evidence supporting the notion that prolonged COVID-19 is equated to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS). Both prolonged COVID-19, ME and CFS are heterogeneous and difficult to characterize, and while some patients with prolonged COVID-19 syndrome may meet diagnostic criteria for EM/CFS, there is a significant population with persistent fatigue that does not meet these criteria; therefore, further research is needed. Identification between the two syndromes could constitute a risk of avoiding other pathologies, complications or sequelae or erring in the management of the syndrome."