COVID-19 is a highly transmittable and pathogenic viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The disease often leads to a cytokine storm, characterized by elevated levels of proinflammatory cytokines, which can result in multiorgan dysfunction. Natural killer (NK) cells, lymphocytes of the innate immune system, play a key role in the defense against viral infections. While studies have shown that NK cells exhibit an altered phenotype and impaired functionality during COVID-19, their exact contribution to the disease’s pathogenesis remains unclear. The aim of our present study was to elucidate the relationship between NK cell population dynamics and COVID-19 severity, from mild to critical cases. For that, we studied a cohort of COVID-19 patients, analyzed their levels of IL-15, TGF-β, PlGF, and GDF-15 in plasma and performed multiparametric flow cytometry phenotypic studies. Our findings revealed that severe COVID-19 patients exhibited elevated plasma levels of IL-15, PlGF, and GDF-15, while TGF-β remained unchanged. Flow cytometry studies demonstrated an enrichment of a NK cell subset expressing the CD151 tetraspanin, which correlated with IL-15 plasma levels and disease severity. This CD151+ subset displayed an activated phenotype, characterized by increased expression of HLA-DR, CD38, and granzyme B. This subset also showed a distinct receptor repertoire (CD160, CD31, and CD55) and higher expression of tissue-resident markers CD103 and CD9 (NK cell decidual marker). Furthermore, we observed an expansion of a CD151^brightCD9+ NK cell subset in individuals with severe disease, suggesting a specific role in COVID-19 pathogenesis. Altogether, our findings indicate that CD151+ NK cells may play a crucial role in COVID-19 immunopathogenesis, providing new insights into future therapeutic strategies targeting NK cell subsets.