Currently, no immunomodulatory agents have been conclusively shown to benefit severe influenza. The World Health Organization conditionally advises against the use of systemic corticosteroids, macrolides, plasma therapy, mechanistic target of rapamycin inhibitors, and nonsteroidal anti-inflammatory drugs for such patients. High-dose systemic corticosteroids may increase mortality and morbidity in severe influenza; the potential of low-dose corticosteroids merits further study given survival benefits in patients with severe coronavirus disease 2019 (COVID-19). Passive immunotherapy using convalescent plasma or intravenous immunoglobulin (IVIG) from healthy donors has not proven effective, suggesting that future research should focus on hyperimmune plasma or IVIG from recent infections. An open-label randomized controlled trial (RCT) found that a triple combination of oseltamivir, clarithromycin, and naproxen improved outcomes in severe influenza. One RCT has indicated that sirolimus with corticosteroids can expedite liberation from mechanical ventilation and reduce viral load, warranting larger trials of sirolimus alone. In contrast, adding macrolides or nitazoxanide has not consistently improved clinical outcomes. Promising evidence exists for anti-C5a antibodies in COVID-19, while case reports hint that intravenous N-acetylcysteine may benefit severe influenza pneumonia. Observational data on statins remain conflicting. Further studies on COX-2 inhibitors in combination with antivirals and other immunomodulators are needed. Mycophenolic acid, pamidronate, and peroxisome proliferator-activated receptor gamma agonists are low priorities due to toxicity concerns. Research into human mesenchymal stromal cells and herbal medicine remains inconclusive. Overall, these findings support large-scale trials to validate promising results and address limitations in small studies. Treatment of severe influenza requires a multidisciplinary approach that integrates antiviral and immunomodulatory strategies. Clarifying these roles may enhance patient outcomes.