Increased expression of interferon (IFN)-stimulated genes (ISGs) in peripheral blood, has been previously reported in viral infections, as well as in autoimmune disorders, in association with reduced leukocyte and platelet counts. Though cytopenias are common in patients with COVID-19 disease and predict severe outcomes, the underlying mechanisms have not been fully elucidated. In the current study, we aimed to determine the prevalence of hematological abnormalities in the setting of active COVID-19 infection and to explore whether they associate with disease outcomes and activation of type I IFN pathway. One-hundred-twenty-three consecutive SARS-CoV2 infected patients were included in the study. Clinical and laboratory parameters were recorded for all study participants. In 114 patients, total RNA was extracted from whole peripheral blood and subjected to real time PCR. The relative expression of three interferon stimulated genes (ISGs; IFIT1, MX-1, and IFI44) was determined and a type I IFN score reflecting peripheral type I IFN activity was calculated. The rates of anemia, leukopenia, and thrombocytopenia were 28.5, 14.6, and 24.4%, respectively. Among leukocytopenias, eosinopenia, and lymphopenia were the most prominent abnormalities being found in 56.9 and 43.1%, respectively. Of interest, patients with either eosinopenia and/or thrombocytopenia but no other hematological abnormalities displayed significantly increased peripheral type I IFN scores compared to their counterparts with normal/high eosinophil and platelet counts. While eosinopenia along with lymphopenia were found to be associated with increased risk for intubation and severe/critical disease, such an association was not detected between other hematological abnormalities or increased type I IFN scores. In conclusion, hematological abnormalities are commonly detected among patients with COVID-19 infection in association with severe disease outcomes and activation of the type I IFN pathway.