Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) considered a global pandemic that threatens worldwide health and economy. Outbreaks of such emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. with neither vaccine nor drugs are currently approved for it, the treatment is basically supportive and symptomatic and that explain why the treatment of this novel virus is very difficult. Repurposing of approved pharmaceutical drugs for new indications presents an ideal alternative solution. Recently, a published study is discussed about the use of Chloroquine and Hydroxychloroquine which are anti-malarial drugs and then the addition of antibiotics drugs such as Azithromycin which is one of the macrolide antibiotics as a combination with HCQ regimen. One of the limitations of it is increase the risk of a polymorphic ventricular arrythmia (TdP) that may be serious and potentially life-threatening. So, we looking for a safer option as Azithromycin monotherapy. In this review there will be a full elucidation behind the selection of a high dose of Azithromycin monotherapy as a potential red blood cell invasion inhibitor in COVID-19 infected patients based on studies and clinical trial showed its efficacy in such similar mechanism as in the treatment of malarial merozoites RBC invasion.