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BACKGROUND: Since the epidemic continues, there is a pressing need to improve our understanding of coronavirus disease 2019 (COVID-19). Mendelian randomization (MR) studies provide us with a method to explore the causality between circulating proteins and COVID-19 susceptibility and severity. We aim to find new perspectives on the pathological mechanism of the disease and possible drug targets for treatment based on this study. METHODS: We conducted a phenome-wide MR study to prioritize circulating proteins causally associated with COVID-19 susceptibility, which was defined as “patients tested positive for COVID-19 vs. population controls”, and severity, which was defined as “patients hospitalized with COVID-19 vs. population controls”. And we repeated the analysis for different definition of COVID-19 susceptibility, severity and control groups. RESULTS: Association of three circulating proteins with COVID-19 susceptibility and severity were demonstrated via our study. C-C motif chemokine 4 (OR =1.887, 95% CI: 1.608–2.165, P=8.04×10(−6)) and 2'-5'-oligoadenylate synthase 1 (OR =0.511, 95% CI: 0.266–0.757, P=8.51×10(−8)) were found respectively positively and negatively correlated with increased COVID-19 severity. Tissue factor, contrary to previous studies, was found associated with decreased COVID-19 susceptibility (OR =0.667, 95% CI: 0.484–0.850, P=1.47×10(−5)) and decreased COVID-19 severity (OR =0.459, 95% CI: 0.132–0.786, P=3.01×10(−6)). CONCLUSIONS: Genetic evidence supports C-C motif chemokine 4 as a risk factor for COVID-19 severity, and 2'-5'-oligoadenylate synthase 1 as a protective factor for COVID-19 severity. The causal association between tissue factor and COVID-19 is contrary to the previous studies, needing further analyses. Further research is warranted to assess the viability of C-C motif chemokine 4 and 2'-5'-oligoadenylate synthase 1 as well as their downstream pathways as drug targets for anti-inflammatory and anti-virus treatment in severe cases.