Due to the significantly negative impact of the coronavirus (CoV) disease (COVID-19) pandemic on the health of the community and the economy, it remains urgent and necessary to develop a safe and effective treatment method for COVID-19. Huang-Lian-Shang-Qing-Wan (HLSQW) is a herbal formula of traditional Chinese medicine (TCM) that has been applied extensively for treating “wind-heat-associated” symptoms in the upper parts of the body. The objective of the present in silico study was to investigate the potential effects of HLSQW in the context of severe acute respiratory syndrome (SARS)-CoV-2 infection. We analyzed the possible interactions between bioactive compounds within HLSQW on targets that may confer antiviral activity using network pharmacology and pharmacophore-based screening. HLSQW was found to potentially target a number of pathways and the expression of various genes to regulate cell physiology and, consequently, the anti-viral effects against SARS-CoV-2. Bioactive compounds contained within HLSQW may exert combined effects to reduce the production of proinflammatory factors, which may trigger the “cytokine storm” in patients with severe COVID-19. Results from molecular modeling suggested that the bioactive HLSQW components puerarin, baicalin, and daidzin exhibit high binding affinity to the active site of 3-chymotrypsin-like cysteine protease (3CLpro) to form stable ligand-protein complexes, thereby suppressing SARS-CoV-2 replication. In addition, our results also demonstrated protective effects of the HLSQW extract against cell injury induced by the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, against reactive oxygen species production and nuclear factor-κB activity in normal human lung cells in vitro. To conclude, HLSQW is a potential TCM remedy that warrants further study with the aim of developing an effective treatment for COVID-19 in the future.