Increased levels of acute-phase reactants and lymphopenia are predictors of disease severity in coronavirus disease 2019 (COVID-19). This study aimed to investigate the role of apoptosis in the etiology of lymphopenia in patients with COVID-19. This multicentered, prospective, and case-control study was conducted with polymerase chain reaction (+) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and an age–gender-matched control group. Samples were taken at the time of diagnosis and analyzed via flow cytometry within 24 h. The participants' demographic data and initial laboratory tests were also recorded. In total, 33 patients with COVID-19 (mean age = 45.4 ± 17.2) and 25 controls (mean age = 43.4 ± 17.4) participated in the study. All patients were identified as having mild (16), moderate (5), or severe (12) disease severity. Both early and late apoptotic cells in B and T lymphocytes were increased in all patients with COVID-19 (p <.05). Early apoptotic (EA) B and T lymphocytes were also higher in severe cases compared to mild cases (p =.026). There was no significant difference between lymphopenia and apoptosis in patients with COVID-19. However, patients with lymphopenia (n = 14) and severe COVID-19 (p =.013) had increased EA T lymphocytes. This study's results show that B and T lymphocytes' apoptosis increases in patients with COVID-19. In addition, enhanced T lymphocyte apoptosis is associated with disease severity in lymphopenic patients with COVID-19.