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Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID\u201019. These were deduced from the gene expression signature of SARS\u2010CoV\u20102\u2010infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral\u2013host interactome. We also identified immuno\u2010modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID\u201019 patients, based on the transcriptome of ACE2\u2010overexpressing A549 cells. Experiments with Vero\u2010E6 cells infected by SARS\u2010CoV\u20102, as well as independent syncytia formation assays for probing ACE2\/SARS\u2010CoV\u20102 spike protein\u2010mediated cell fusion using HEK293T and Calu\u20103 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero\u2010E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. 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