Background: COVID-19 is a highly pathogenic and transmittable viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). COVID-19 infection has a wide range of severity ranging from an asymptomatic form to a severe form with acute respiratory distress which may lead to death. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcription factor that controls the antioxidant defense system which plays an important role in minimizing the symptoms induced by the cytokine storm in COVID-19. It has been found that miRNAs are involved in the regulation of different viral infections, however, the association between miRNAs and COVID-19 remains to be investigated. Aim: we aimed to investigate the role of miR-142-5p in modulating the inflammatory response in COVID-19 patients through the regulation of Nrf2/Keap1 pathway. Methods: The study was performed on 50 subjects that were divided into 2 groups: 15 healthy control subjects and 35 COVID-19 patients that were subdivided into 20 patients from the ward and 15 from intensive care unit (ICU). Peripheral blood was drawn from all subjects for estimation of gene expression of miRNA-142-5P, ACE2, NF-kβ, Nrf2, Keap-1, and HO-1 by QRT-PCR. Results: The COVID-19 patients showed a highly significant increase in miRNA-142-5p, Keap1, ACE2 and NF-kβ gene expression levels and a highly significant decreased expression levels of Nrf2 and HO-1 as compared to the control group. A highly significant negative correlation was detected between the miRNA-142-5p and Nrf2 expression levels in COVID-19 patients.  Conclusion: Such data suggest that miRNA-142-5p could affect the severity of cytokine storm through its effect on Nrf2/ Keap1 axis. Targeting miRNA-142-5p could be a potential therapeutic approach against COVID-19.