Immunopathogenesis drives both severe acute COVID-19 and postacute sequelae of COVID-19 (PASC). Therefore, dissecting the immune response to SARS-CoV-2, the causative agent of COVID-19, is critical to understand disease pathogenesis and identify pathways targetable by therapeutic intervention. Our lab previously discovered a link between the type 2 cytokine IL-13 and COVID-19 severity, prompting us to investigate drivers of type 2 immunity in COVID-19. The alarmin cytokine IL-33 is a potent inducer of type 2 immunity, as its receptor ST2 is expressed by type 2 cells including type 2 innate lymphoid cells (ILC2s). We therefore sought to investigate IL-33/ST2 signaling in mouse-adapted SARS-CoV-2 MA10 (MA10) infection, a mouse model of COVID-19. In MA10 infection, ST2-/- mice had improved survival as compared to wild-type mice (69.2% vs 13.3% survival; P = 0.0005). In a complementary pharmacologic approach, IL-33/ST2 signaling was inhibited using the helminth-derived protein HpBARI_Hom2. In MA10 infection, HpBARI_Hom2-treated mice had improved survival (60% vs 10% survival; P = 0.0035), and reduced pulmonary pathology as compared to inert control-treated mice. HpBARI_Hom2 treatment did not reduce viral titers, suggesting an immunopathogenic role for IL-33/ST2 signaling independent of viral control. In MA10 infection, HpBARI_Hom2-treated mice had reduced IL-5 in bronchoalveolar lavage fluid and reduced IL-13 expression by pulmonary ILC2s, suggesting activation of ILC2s may be a mechanism through which IL-33/ST2 signaling drives pathogenesis. To test whether IL-33-activated ILC2s were sufficient to drive severe disease, we employed an adoptive transfer model and found that transfer of ST2+ ILC2s to ST2-/- mice did indeed increase pulmonary pathology during MA10 infection. Future work will investigate how IL-33/ST2 signaling impacts extracellular matrix composition, as we have also found HpBARI_Hom2 treatment reduces the accumulation of pulmonary hyaluronan during MA10 infection. This research identifies the IL-33/ST2 axis as a potential therapeutic target in treatment of infection-induced pulmonary immunopathogenesis.