The re-emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in Wuhan city of China has placed unprecedented economic and health burden globally. The SARS-CoV-2 high mortality rate has brought great challenges to researchers, clinicians, and health workers in their bid to discover appropriate therapeutic interventions. The search for the ultimate remedy was initially centered on the use of antiviral agents targeting receptors and proteins involved in the pathophysiology of SARS-CoV-2 such as spike (S) proteins, papain-like protease (PLpro), replicase polyproteins 1a, main protease, RNA dependent RNA polymerase (RDRP), RNA binding protein of NSP9, and 3-chymotrypsin-like protease (3CLpro). However, the upsurge of interest in repositioning anti-inflammatory agents was borne out of the revealed role played by cytokine storm in COVID-19 fatality. Hypercytokinemia as a result of the unregulated production of pro-inflammatory cytokines and other chemical mediators trigger coagulopathy, viral sepsis, pneumonitis shock, and acute respiratory syndrome which may lead directly to respiratory and organs failure and ultimately death of patient. Emerging evidence has shown that early prediction of cytokine storm with serum chemistry and hematological markers (D-dimer, ferritin, cytokine, lactate dehydrogenase, C-Reactive proteins, alanine aminotransferase, neutrophil/lymphocyte ratio, and erythrocyte sedimentation rate) and the use of an appropriate anti-inflammatory agents (synthetic drugs, biologicals and herbal products) will nip cytokine storm on the bud thereby averting COVID-19 fatality. A wide array of targets will arrest cytokine storm such as the use of inhibitors of interleukin-1-beta converting enzyme (caspase-1), beta-2-adrenergic receptors (ADRB₂), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), interferons (IFNs), Janus kinase (JAKs) as well as interleukin -6 (IL-6). This review critically used information retrieved from PubMed, China National knowledge infrastructure, Embase, Medline, and Google Scholar to elaborate the therapeutic interventions for COVID-19, highlighted shortfalls of some of the interventions, and way forward for discovering effective biocompatible drug target.