Recently an anti-COVID-19 therapeutic application of the drug 2-deoxy-D- glucose (2-DG) an analogue of glucose has been developed in collaboration between Institute of Nuclear Medicine and Allied Sciences (INMAS), India, Defence Research and Development Organisation (DRDO), India, and Dr Reddy’s Laboratories (DRL), India. As per the reports 2-DG is effective against SARS-COV- 2. Publication of phase 2 and phase 3 clinical trial data is pending. However, it has been shown that 2-DG reduces the supplemental oxygen dependence on covid-19 infected patients and make their recovery faster. The present outbreak of Covid-19 infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major menace to human being. As the understanding of the mechanism of the therapeutic action of 2-DG on SARS-CoV-2 infected hosts is missing, in this work we have studied the possible inhibitory interaction of the drug with two different pathways (a) with non-structured viral proteins involved in translation and replication of SARS-CoV-2 and (b) its inhibition mechanism of the glycolysis pathway. We have used our fully automated novel drug designing platform with state-of-the-art free energy of binding calculator PRinMTML-ESS to evaluate the role of 2-DG as an antiviral and glycolysis pathway inhibitor in SARS-CoV-2 affected humans. Docking, all atom molecular dynamic simulation and enhanced free energy sampling methods used in PRinMTML-ESS have predicted that 2-DG effectively reduced the replication of SARS-CoV-2 in human cell by reducing the glycolytic flux, by competitive inhibition of glucose in binding with the enzyme hexokinase. 2-DG is generally administered in covid patient along with other antivirals and steroid, hence it can be used as a mild clinical therapy which can reduce the viral replication, inflammation when given in the earlier stage of the disease.