The COVID-19 epidemic has already exerted a wide effect on the global level and the rapid growth of infected cases resulted in an overwhelmed health care providing systems. Many countries that have already peaked and flattened the infection curve reached now the minimum infection rate and minimal or zero reporting of new cases. As a consequence, many countries are reducing their precautionary measures which might lead to the emerging of a second incidence wave of SARS-CoV-2. On the other hand, direct antiviral combination therapy as Ledipasvir/Sofosbuvir showed sufficient efficacy in treatment of chronic hepatitis C virus (HCV) with an acceptable safety profile showing a minimum side effect and well tolerated upon administration during the treatment time course as well. Besides, according to published studies and collected data, this combination recorded a minimal drug interactions with the other therapeutic agents used for the management of co-morbid conditions with COVID-19. Finally, the reported results of performed studies showed a superior time to clinical recovery from COVID-19 for Sofosbuvir / Daclatasvir regmin over that of Lopinavir/ritonavir, and thus, the proposal of involving Ledpasvir/Sofosbuvir combination as a better treatment option than other direct antiviral agents in the management of COVID-19 for the second wave.