Objective To evaluate the efficacy and adverse events of immunomodulators in the treatment of severe coronavirus disease 2019 (COVID-19). Methods A literature search for the meta-analysis was performed using PubMed, The Cochrane Library, Embase, Wanfang Data, CNKI, and Web of Science to identify randomized controlled trials assessing the outcomes of patients treated with corticosteroids alone and/or interleukin-6 receptor antagonists for COVID-19. The risk of bias was assessed using the Cochrane method. The protocol was registered with PROSPERO (registry number: CRD42022356904). Results Compared with patients receiving standard of care, patients treated with corticosteroids alone had an increased risk of 14-day in-hospital death, whereas those treated with interleukin-6 receptor antagonists alone or in combination with corticosteroids had a lower risk of 14-day in-hospital death. Corticosteroid therapy alone was associated with increased risk of several adverse events, including intensive care unit admission and non-invasive ventilation, whereas interleukin-6 receptor antagonists alone or in combination with corticosteroids were not linked to adverse effects. Conclusions The findings supported the safety and efficacy of interleukin-6 receptor antagonists, either alone or together with corticosteroids, in patients with severe COVID-19; evidence supporting the efficacy and safety of corticosteroids monotherapy is lacking.