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It has become evident that the actions of pro-inflammatory cytokines and/or the development of a cytokine storm are responsible for the occurrence of severe COVID-19 during SARS-CoV-2 infection. Although immunomodulatory mechanisms vary among viruses, the activation of multiple TLRs that occurs primarily through the recruitment of adapter proteins such as MyD88 and TRIF contributes to the induction of a cytokine storm. Based on this, controlling the robust production of pro-inflammatory cytokines by macrophages may be applicable as a cellular approach to investigate potential cytokine-targeted therapies against COVID-19. In the current study, we utilized TLR2/MyD88 and TLR3/TRIF co-activated macrophages and evaluated the anti-cytokine storm effect of the traditional Chinese medicine (TCM) formula Babaodan (BBD). An RNA-seq-based transcriptomic approach was used to determine the molecular mode of action. Additionally, we evaluated the anti-inflammatory activity of BBD in vivo using a mouse model of post-viral bacterial infection-induced pneumonia and seven severely ill COVID-19 patients. Our study reveals the protective role of BBD against excessive immune responses in macrophages, where the underlying mechanisms involve the inhibition of the NF-κB and MAPK signaling pathways. In vivo, BBD significantly inhibited the release of IL-6, thus resulting in increased survival rates in mice. Based on limited data, we demonstrated that severely ill COVID-19 patients benefited from BBD treatment due to a reduction in the overproduction of IL-6. In conclusion, our study indicated that BBD controls excessive immune responses and may thus represent a cytokine-targeted agent that could be considered to treating COVID-19. [Display omitted] • Cytokine-targeted therapeutic strategies to reduce lung inflammatory injury have been proposed for the treatment of patients with severe COVID-19. • TCM within the "heat-clearing and detoxifying (qingre jiedu)" category have been demonstrated to exert strong anti-inflammatory activities. • Baobadan (BBD) exerts pronounced anti-inflammatory effects on TLR1/2 and TLR3 dual activated macrophages that are associated with NF-κB and MAPKs. • BBD protects mice from excessive cytokine production and inflammatory lung injury. • Based on limited data, BBD appears to reduce the overproduction of IL-6 in severely ill COVID-19 patients. [ABSTRACT FROM AUTHOR]