Viruses targeting respiratory tract have significant impact on pulmonary function. Coronavirus disease 2019 (COVID-19) is one of the newly emerged respiratory tract viral infection. Pandemic COVID-19 has caused significant impact on clinical and economic consequences all over the globe. As the process of developing a new drug or a vaccine takes from months to years, it is a pressing need to look for an already existing drug that has the potentiality to work in a prophylactic manner in ambulatory peoples who are at high risk of developing SARS-COV-2. Prevention of the disease is a better option than treating it. World Health Organization WHO recommends prevention strategies like distancing, home isolation, people education, and wearing gloves and mask for suspected COVID-19 patients. COVID-19 has devastating impacts on clinical and economy. Healthcare team and individuals that help in delivery of care to patients all are at high risk for infection. It has rapid human-human horizontal transmission. An idea of using Azithromycin (an approved inveterate drug) in a specific dose and special designed regimen as a prophylaxis for SARS-COV-2 rather than treatment has emerged to light. In this review we will demonstrate the reasons behind the selection of Azithromycin rather than other antibiotics, its advantage that has made it a reasonable candidate to be given as a prophylactic agent against the virulent COVID-19, and its potential mechanism as anti-inflammatory and immune-modulatory agent in reducing the probability of COVID-19 in infecting ambulatory people who are at serious risk.