The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56−T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56+T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8+T cells, mainly due to the CD56−cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8+T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3+and NKp30+cells in the CD56+T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D+and NKG2A+cells and increased PD-1 and HLA-DR expression levels were found in both CD56−and CD56+T cells, and can be considered as indicators of COVID-19 progression. In the CD56−T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56−CD16+T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56+T cells in COVID-19.