Protein glycosylation is one of the most vital modifications. Understanding the role of protein glycosylation in coronavirus disease 2019 (COVID-19) is the key in elucidating its pathogenesis and developing therapeutic strategies. We conducted a case-control study to examine the total fucosylation levels and the levels of individual immunoglobulin G (IgG) subtypes in the serum of COVID-19 patients. Notably, we identified 13 glycosyltransferase-related and glycosidase-related genes displaying differential expression among COVID-19 patients. Our findings from the detection of serum fucosylation levels in COVID-19 patients revealed a diminished degree of glycosylation. Furthermore, the analysis of the levels of different IgG subtypes revealed an increase in IgG1 fucosylation and a decrease in IgG2 fucosylation, with the latter being linked to patients’ body temperature and disease progression. The change in COVID-19 disease severity from mild to severe may be related to fucosylation. The single-cell sequencing analysis revealed the expression of members of the fucosyltransferase family in the plasma cells and plasmablasts of COVID-19 patients. We leveraged the recommended medication for severe COVID-19, Fuzheng Jiedu Decoction (FZJDD), to confirm the importance of fucosylation in severe COVID-19. The network pharmacology analysis of FZJDD revealed that fucosylation inhibition might contribute to its antiviral effects against COVID-19. We assessed the efficacy of this compound in septic mice, by monitoring serum fucosylation levels, and found that FZJDD significantly alleviated inflammation in lipopolysaccharide (LPS)-induced septic mice. Concurrently, the analysis of plasma fucosylation levels in septic mice indicated a marked decrease in total fucosylation. The glycan analysis revealed the involvement of α1,6-fucosyltransferase (FUT8) and α-L-fucosidase 1 (FUCA1), a pair of interacting fucosidases, in COVID-19 pathogenesis. This study revealed substantial alterations in fucosylation among patients with severe COVID-19, with the primary variations observed in the IgG2 subtype. These changes are intricately coordinated by the mutual regulation of the FUT8 and FUCA1 enzymes. Furthermore, the endorsement of FZJDD as a recommended therapeutic option for severe COVID-19 underscores the promising potential of defucosylation as a viable treatment strategy for this disease.