: Isofraxidin is a hydroxylcoumarin derived from herbal Fraxinus and Eleutherococcus. It has been shown that isofraxidin has antioxidant, anti-inflammatory, anti-diabetic, and anti-lipidemic effects. The study aimed to examine the therapeutic effects of isofraxidin with and without methylprednisolone to ameliorate lipopolysaccharide (LPS)-induced cytokine-releasing syndrome. : The study comprised two phases: preventive and therapeutic. In all the experiments that involved LPS induction, a single dose of LPS (5 mg/kg) was used. The preventive phase involved the administration of the agents before LPS induction, in which 50 mg/kg of methylprednisolone, 15 mg/kg of isofraxidin, or a combination of 7.5 mg/kg of isofraxidin plus 25 mg/kg methylprednisolone were given daily for 3 days before induction. The therapeutic phase involved the administration of the following agents after LPS induction: 50 mg/kg methylprednisolone, 15 mg/kg of isofraxidin, or a combination of 7.5 mg/kg of isofraxidin plus 25 mg/kg methylprednisolone were given once daily was given for 7 days. : Isofraxidin treatment with or without methylprednisolone ameliorates LPS-induced inflammatory and oxidative stress damage in mice; it reduces the inflammatory (IL-6, TNF-α, IL-1β, IL-8, Malondialdehyde, and IFN-γ) and oxidative stress markers. Additionally, isofraxidin treatment with or without methylprednisolone prevented liver and lung tissue damage induced by LPS. : Isofraxidin exhibited preventive and therapeutic properties against lipopolysaccharide-induced cytokine storms in mice via anti-inflammatory and antioxidant pathways, and its combination with methylprednisolone demonstrated synergistic outcomes.