Cytokines, the main players in the cytokine storm, can act as immunomodulators regulating inflammatory responses. S. baicalensis active components (SBACs) can act directly on immune cells such as lymphocytes, macrophages, mast cells, dendritic cells, monocytes, and neutrophils, and inhibit the production of inflammatory cytokines and alleviate inflammatory damage to organ tissues. “→”, promotion; “▪”, inhibition. Display omitted •Infection-associated cytokine storms can readily lead to organ failure or death.•The bioactive substances of S. baicalensis act directly on multiple immune cells.•The bioactive substances inhibit the production of diverse inflammatory cytokines.•The immunomodulatory mechanisms include multiple inflammatory signaling pathways.•S. baicalensis active components are potential drugs for cytokine storm treatment. Scutellaria baicalensis Georgi., a plant used in traditional Chinese medicine, has multiple biological activities, including anti-inflammatory, antiviral, antitumor, antioxidant, and antibacterial effects, and can be used to treat respiratory tract infections, pneumonia, colitis, hepatitis, and allergic diseases. The main active substances of S. baicalensis, baicalein, baicalin, wogonin, wogonoside, and oroxylin A, can act directly on immune cells such as lymphocytes, macrophages, mast cells, dendritic cells, monocytes, and neutrophils, and inhibit the production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and other inflammatory mediators such as nitric oxide, prostaglandins, leukotrienes, and reactive oxygen species. The molecular mechanisms underlying the immunomodulatory and anti-inflammatory effects of the active compounds of S. baicalensis include downregulation of toll-like receptors, activation of the Nrf2 and PPAR signaling pathways, and inhibition of the nuclear thioredoxin system and inflammation-associated pathways such as those of MAPK, Akt, NFκB, and JAK-STAT. Given that in addition to the downregulation of cytokine production, the active constituents of S. baicalensis also have antiviral and antibacterial effects, they may be more promising candidate therapeutics for the prevention of infection-related cytokine storms than are drugs having only antimicrobial or anti-inflammatory activities.