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Background Coronavirus disease 2019 (COVID-19) is characterized by immune-mediated lung injury and complex alterations of the immune system, such as lymphopenia and cytokine storm, that have been associated with adverse outcomes underlining a fundamental role of host response in severe acute respiratory syndrome coronavirus 2 infection and the pathogenesis of the disease. Thymosin alpha 1 (Tα1) is one of the molecules used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancer. Methods In this study, we captured the interconnected biological processes regulated by Tα1 in CD8+ T cells under inflammatory conditions. Results Genes associated with cytokine signaling and production were upregulated in blood cells from patients with COVID-19, and the ex vivo treatment with Tα1-mitigated cytokine expression, and inhibited lymphocyte activation in a CD8+ T-cell subset specifically. Conclusion These data suggest the potential role of Tα1 in modulating the immune response homeostasis and the cytokine storm in vivo., Graphical Abstract Graphical Abstract, Tα1 restores dysregulated pathways under proinflammatory conditions. Tα1 inhibits cytokine-related gene expression in blood cells from COVID-19 individuals. Tα1 disrupts cytokines and T-cell activation in COVID-19. Modulation of CD38 in CD8+ T cells by Tα1 depends on the clinical score.