Introduction A new coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), was first reported to cause human infection in Wuhan, China, in December 2019. The virus by now has been detected in all continents except Antarctica. The name represents the form of “corona,” from the many crown-like spike proteins on the surface of the virus. These spikes thought to be the main domain in connection to angiotensin-converting enzyme 2 (ACE2) on the cell surface; therefore, the mechanism of virus entry is already hypothesized. There are disagreements about the use of the renin-angiotensin-aldosterone system (RAAS) inhibitors that may alter ACE2 expression. Therefore, the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) and the consequent dynamics in ACE2 expression might affect the virulence and the outcome of the infection. Coronavirus disease-19 (COVID-19) is a pandemic with significant mortality. One of the critical comorbidities leading to adverse outcomes is cardiovascular disease (CVD). Patients with cardiovascular diseases (CVDs) are often treated with ACEIs and ARBs acting on RAAS. ACEIs and ARBs might upregulate the expression of ACE2, providing more gates to the virus to enter the cells; they also exert beneficial hemodynamic, anti-inflammatory, and tissue-protective effects. Given the frequent use of ACEIs and ARBs worldwide, evidence-based recommendations on the use of these agents in patients with COVID-19 is urgently needed. Aim First, we aim to investigate the effects of ACEIs and ARBs on ACE2 activity and expression in experimental in vitro and in vivo animal models. Second, we will examine the impact of ACEIs and ARBs on the reported outcomes of COVID-19 involving patients’ data. Scientific questions in the systematic review on experimental data are: Whether the angiotensin-converting enzyme inhibitors and angiotensin receptor blockers could influence the expression of the ACE2? What is the tissue distribution of ACE2? What is the role of ACE2 in different pathological conditions (myocardial hypoxia, hypertension, heart failure, inflammatory diseases, oxidative stress, etc.)? How does ACE2 influence the expression dynamics of angiotensin-like peptide levels (Angiotensin 1-7, Angiotensin 1-9)? Scientific questions in the systematic review or meta-analysis on clinical data is: Do ACEIs and ARBs have any effect on the outcome of the infection? Finally, we aim to integrate the findings of both systematic reviews and interpret the experimental data in light of the clinical result. Methods Two separate systematic reviews and -if possible -a clinical meta-analysis will be performed to answer the questions mentioned above. Data We plan to include published data in peer-reviewed scientific papers. In consideration of the contemporary importance of COVID-19, we keep on systematic screening the publications daily and involve relevant papers to our study. Two independent review teams will perform each systematic review. In each independent review team, two independent reviewers will make the selection by title, abstract, and full text. The disagreements between the independent reviewers will be resolved through consensus and discussion involving the senior leaders of each systematic review team.