The novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious threat to global public health. Respiratory failure followed by cardiovascular complications with wide-spread endothelial dysfunction and inflammation is rapidly emerging as a key threat in COVID-19. ACE-2 receptors are the cell-entry gate for SARS-CoV-2. Valproic Acid (VPA) is a proposed potential drug to treat COVID-19 but its mechanism of action is not well understood. We demonstrate that VPA-treatment significantly reduced ACE-2 expression in endothelial cells. VPA-treatment significantly reduced the expression of inflammatory cytokines IL-6 along with the endothelial activation marker ICAM-1. We provide evidence and discuss the plausible mechanism in detail for VPA use to prevent and treat COVID-19 in a personalized manner. Our study is expected to entice the scientific and clinical society to investigate VPA as a potential therapeutic option against COVID-19.