Background: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 patients as painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most potent NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology.Method: FDA (U.S. Food & Drug Administration) approved twenty NSAIDs were used for this study. Genes related to selected NSAIDs and COVID-19 related genes were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases. Venn diagram identified overlapping genes between NSAIDs and COVID-19 related genes. The interactive networking between NSAIDs and overlapping genes was analyzed by STRING. RStudio plotted the bubble chart of KEGG pathway enrichment analysis of overlapping genes. Finally, the binding affinity of NSAIDs against target genes was determined through molecular docking analysis.Results: Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD genes were explored as the associated genes of the RAS. Among twenty NSAIDs, 6MNA, rofecoxib, and indomethacin revealed promising binding affinity with the highest docking score against three identified genes, respectively.Conclusions: Overall, our proposed three NSAIDs (6MNA, rofecoxib, and indomethacin) might block the RAS by inactivating its associated genes, thus may alleviate excessive inflammation induced by SARS-CoV-2.