Here, we identified methotrexate as a multi-target drug: 1) inhibits SARS-CoV-2 entry, 2) reduces virus replication (via pyrimidine metabolism), and 3) diminishes the inflammatory monocyte-driven cytokine storm (via IL-17 signaling) to reduce NETs formation associated thrombosis (via complement and coagulation cascades) and lymphopenia (via T cell receptor signaling) (Figure 6). This evidence concerns the gene IL17A and lymphopenia.