BACKGROUND AND PURPOSE:: Accumulating evidence suggests circulating microRNAs (miRNAs) are important regulators of biological processes involved in COVID-19 complications. We sought to assess whether circulating miRNAs are associated with COVID-19 clinical phenotype and outcome. EXPERIMENTAL APPROACH:: To discover signatures of circulating miRNAs associated with COVID-19 disease severity and mortality, miRNA quantification was performed on plasma samples collected at hospital admission from a cohort of 106 patients with mild or severe COVID-19. Variable importance projection scoring with partial least squared discriminant analysis and Random Forest Classifier were employed to identify key miRNAs associated with COVID-19 severity. ROC analysis was performed to detect promising miRNA able to discriminate between mild and severe COVID status. KEY RESULTS:: Hsa-miR-1-3p was the most promising miRNA in differentiating COVID-19 patients who developed severe, rather than mild, disease. Hsa-miR-1-3p levels rose with increasing disease severity, and the highest levels were associated with prolonged hospital length of stay and worse survival. Longitudinal miRNA profiling demonstrated that plasma hsa-miR-1-3p expression levels were significantly increased in patients during acute infection compared with those observed 6 months after the disease onset. Specific blockade of miR-1-3p in SARS-CoV-2–infected endothelial cells decreased up-regulation of genes involved in endothelialto-mesenchymal transition, inflammation and thrombosis. Furthermore, miR-1-3p inhibition reversed the impaired angiogenic capacity induced by plasma from patients with severe COVID-19. CONCLUSION AND IMPLICATIONS:: Our data establish a novel role for miR-1-3p in the pathogenesis of COVID-19 infection and provide a strong rationale for its usefulness as early prognostic biomarkers of severity status and survival.