•Circulating microRNA (miRNA) are biomarkers of tissue injury or host response to an infection.•We found significant alterations in serum miRNA profile in a mouse model of Crimean-Congo haemorrhagic fever.•Some miRNA profiles were close to those reported in other haemorrhagic fever illness or tissue injury.•A combination of 8 miRNAs allowed a 100% discrimination of mice developing a severe illness from control mice. Crimean-Congo haemorrhagic fever (CCHF) is a severe disease leading to high mortality in humans. Early diagnosis and evaluation of the severity are necessary to improve patient survival. In a model of CCHF virus-infected interferon-receptor-deficient (IFNAR) KO mice, we found a specific circulating miRNA (c-miRNA) profile when compared to wild-type (wt), resistant mice. Among this response, 20 c-miRNA were shown to be specifically altered, including miR-122-5p, miR-216a-5p, 217-5p, miR-29a-3p and miR-511-5p. Using a logistic regression analysis, a combination of 8 miRNAs allowed a 100% discrimination of mice developing a severe illness (IFNAR-KO) from non-detectable clinical signs (wt).