In summary, our multi-scale modeling approach provides evidence that the prodrug tenofovir-disoproxil fumarate is a potential candidate to limit disease severity due to SARS-CoV-2 and might maximize its impact when given as prophylaxis; when evaluated in clinical trials, it is expected that its efficacy might depend on the relative time from infection to drug administration as well as for individual PK/PD factors conditioning distribution in SARS-CoV-2 targeted cells. Our work provides a mechanistic explanation of the observed clinical effect of TDF against COVID-19 and can help optimize the evaluation of antiviral therapies for COVID-19, in particular those targeting the RNA dependent RNA polymerase.