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Acute respiratory distress syndrome (ARDS) is intricately linked with SARS-CoV-2-associated disease severity and mortality, especially in patients with co-morbidities. Lung tissue injury caused as a consequence of ARDS leads to fluid build-up in the alveolar sacs, which in turn affects oxygen supply from the capillaries. ARDS is a result of a hyperinflammatory, non-specific local immune response (cytokine storm), which is aggravated as the virus evades and meddles with protective anti-viral innate immune responses. Treatment and management of ARDS remain a major challenge, first, because the condition develops as the virus keeps replicating and, therefore, immunomodulatory drugs are required to be used with caution. Second, the hyperinflammatory responses observed during ARDS are quite heterogeneous and dependent on the stage of the disease and the clinical history of the patients. In this review, we present different anti-rheumatic drugs, natural compounds, monoclonal antibodies, and RNA therapeutics and discuss their application in the management of ARDS. We also discuss on the suitability of each of these drug classes at different stages of the disease. In the last section, we discuss the potential applications of advanced computational approaches in identifying reliable drug targets and in screening out credible lead compounds against ARDS.