Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron has demonstrated decreased pathogenicity, yet a few individuals suffer severe pneumonia from coronavirus disease 2019 (COVID-19) infection; the underlying mechanisms are unknown. Methods The present work investigated the role of Interferon-stimulated genes (ISGs) in the occurrence and progression of severe Omicron infection. The expression and dynamic changes of ISGs were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), and the anti-ISG15 autoantibody in infected patients was detected by ELISA. Moreover, we evaluated the correlation of ISGs with disease severity and outcomes by comparing expression of ISGs among each group. Results Decreased expression of several ISGs such as IFI6 are potentially linked to increased severity or poor outcomes of Omicron infection. Longitudinal data also demonstrates that the dynamic variation of IFI6 in the Omicron infection phase may be linked to the prognosis of the disease. The increase of anti-ISG15 autoantibody potentially links to the disease progression and poor outcome of patients with high level of ISG15 expression. Conclusions These findings define aberrant Interferon-stimulated gene associated host responses and reveal potential mechanisms and therapeutic targets for Omicron or other viral infection.