INTRODUCTION: The COVID-19 pandemic remains a global challenge . While there are mRNA agents on the horizon as a potential prevention, a definitive drug therapy is an unmet medical need . The hyperinflammatory response, known as the 'cytokine storm', is chiefly responsible for complications and deaths . The binding of spike-glycoprotein of SARS-CoV-2 to TLR4 receptors has been documented in several studies and has been found to play a role in hyperinflammation, hence there is an interest in TLR4 as a potential drug target.Areas Covered: This review discusses the neurological and respiratory complications of SARS-CoV-2 infection and progresses to examine the role of the 'cytokine storm' and the involvement of TLR4 receptors in these complications . The possibility of using TLR4 modulators to curb the complications are considered and finally, a short perspective on future potential drug treatments is offered . Various databases were searched including Pub-Med, Google Scholar, and Medline . The search mainly included research articles, meta-analysis, retrospective studies, reports, and systematic reviews.Expert Opinion: TLR4 modulators are being investigated in clinical trials for COVID-19 . Challenges in terms of structural diversity of the agents, their natural origin and efficacy demand extensive research.