The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective preventive and therapeutic drugs are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Gansu Fangji has been used in a wide range of clinical applications for COVID-19 therapy with excellent antiviral and anti-inflammatory effects. Here, an chemical biological information strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Gansu Fangji. Overall, potentially active compounds that can bind well to antiviral and anti-inflammatory related targets such as IL-6R and S protein were screened from Gansu Fangji's compound structure library by molecular docking, and were confirmed have a good binding affinity for target protein by Microscale thermophoresis (MST) assay or SPR assay. Network pharmacology was used to further analyze the mechanism of action of these potential compounds. Furthermore, the anti-inflammatory effects of these compounds were verified by in vivo and ex vivo experiments in mice, respectively. The antiviral activity of these compounds was also verified by live virus assays. We screened active anti-inflammatory and antiviral compounds through the above experiments and validated their molecular mechanisms in cellular models and transgenic Drosophila. These results provide an important basis for the clinical application of traditional Chinese medicine to prevent and remediate COVID-19.