The clinical efficacy of biological immunomodulators in patients refractory to standard therapy of intravenous immunoglobulin (IVIg) and glucocorticoids remains unclear. This review aimed to outline real-world data on the clinical outcomes of biological immunomodulators using Ovid-Medline, EMBASE, Cochrane CDSR, and the Korean database, KMBASE from September 2021 to August 2022. Among 251 studies , 10 were selected, of which two were observational studies with control groups receiving a standard therapy of IVIg and/or glucocorticoids. In total, 145 patients were treated with biological agents. In the first study with a control group, anakinra-treated group exhibited a lower left ventricular ejection fraction at baseline (54% vs. 60%, P = 0.08). Patients in the infliximab group of second study showed lesser additional treatment requirements (31% vs. 65%, P = 0.01), and lower rate of newly developed left ventricular dysfunction (4% vs. 20%, P = 0.05). The remaining eight single-arm studies did not report the clinical outcomes of each type of biological immunomodulator individually, limiting further interpretation. The findings of this review imply the potential of biological immunomodulators as a feasible therapeutic option for refractory MIS-C.