Severe acute respiratory syndrome caused by coronavirus 2 emerged in Wuhan (China) in December 2019 and has severely challenged the human population. NK and T cells are involved in the progression of COVID-19 infection through the ability of NK cells to modulate T-cell responses, and by the stimulation of cytokine release. No detailed investigation of the NK cell landscape in clinical SARS-CoV-2 infection has yet been reported. A total of 35 COVID-19 hospitalised patients were stratified for clinical severity and 17 healthy subjects were enrolled. NK cell subsets and T cell subsets were analysed with flow cytometry. Serum cytokines were detected with a bead-based multiplex assay. Fewer CD56dimCD16brightNKG2A+NK cells and a parallel increase in the CD56+CD69+NK, CD56+PD-1+NK, CD56+NKp44+NK subset were reported in COVID-19 than HC. A significantly higher adaptive/memory-like NK cell frequency in patients with severe disease than in those with mild and moderate phenotypes were reported. Moreover, adaptive/memory-like NK cell frequencies were significantly higher in patients who died than in survivors. Severe COVID-19 patients showed higher serum concentrations of IL-6 than mild and control groups. Direct correlation emerged for IL-6 and adaptive/memory-like NK. All these findings provide new insights into the immune response of patients with COVID-19. In particular, they demonstrate activation of NK through overexpression of CD69 and CD25 and show that PD-1 inhibitory signalling maintains an exhausted phenotype in NK cells. These results suggest that adaptive/memory-like NK cells could be the basis of promising targeted therapy for future viral infections.