The most serious health issue today is the rapid outbreak of Coronavirus Disease 2019 (COVID-19 or SARS-CoV-2). It is now a global pandemic and is a huge concern for public health. So far, more than 3,500,000 confirmed cases were diagnosed in nearly 212 countries and territories around the world and 2 international conveyances, causing globally over 250,000 deaths. Epidemiology, risk factors, and clinical characteristics of COVID-19 patients have been identified but the factors influencing the immune system against COVID-19 have not been well established. Currently, the adenosine pathway is seen as a major obstacle to the efficacy of immune therapies and is an important therapeutic target for cancer and microbial infections. Pharmacologic inhibitors or antibodies specific to adenosine pathway components or adenosine receptors in microbial and tumor therapy have shown efficacy in pre-clinical studies and are entering the clinical arena. In this review, I propose a novel hypothesis explaining the potential for improving the efficiency of innate and adaptive immune systems by co-inhibition of CD73 and A2AR adenosine Signaling for COVID-19 prevention and control.