Background: The role of Ivermectin in improving the outcome of coronavirus disease of 2019 (COVID-19) symptoms was reported in several studies, while its effect on the pro-inflammatory cytokines triggering the cytokine storm is still not investigated. Method: This study aimed to investigate the role of Ivermectin on the proinflammatory cytokines in Covid-19 patients and correlated the results with the expression of miR-2909, miR-223-3p. Three hundred and twenty hospitalized patients with confirmed moderate-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were selected. The patients were divided into 2 groups: Group I treated with the Egyptian protocol of COVID-19 including (Ivermectin plus hydroxychloroquine). Group II was treated with the Egyptian protocol, including hydroxychloroquine and no Ivermectin. IL-6, IL-1b, procalcitonin, and gene expression of miR-2909, miR-223-3p, and Toll-like receptor 4 were done by real-time Polymerase Chain Reaction (PCR). Results : Patients treated with COVID-19 protocol including Ivermectin showed a significant decrease of cytokines levels (IL-6, IL-1, and procalcitonin), when compared with the other group, the cytokines levels improvement were positively correlated with miR-2029 expression and negatively correlated with the expression of miR-223-3p. Moderate ill COVID-19 patients treated with Ivermectin showed a significant decline in mortality rate and duration of hospital stay. Conclusion: Ivermectin is an effective drug in improving the outcome of SARS-CoV-2 patients with a significant decrease in mortality rate through decreasing cytokines expression via controlling miR-2029, miR-233-3p expressions. Keywords: SARS-CoV-2; Ivermectin; miR-223-3p; miR-2029; Covid-19; Cytokines.