Dysregulated activation of the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) signaling pathway is strongly associated with inflammatory and autoimmune disorders, which positions the pathway as a promising therapeutic target. Given the current lack of approved inhibitors or monoclonal antibodies targeting IL-21/IL-21R, we employed a structure-based virtual screening strategy coupled with experimental validation to identify potential IL-21 antagonists from a library of marine natural products provided by TargetMol. Our investigation identified fucoxanthin, a marine-derived carotenoid, as a potent binder to IL-21R, exhibiting a docking score of ?8.19?kcal/mol. Molecular dynamics simulations further confirmed the stability of the IL-21R–fucoxanthin complex, with a calculated binding free energy (ΔG) of ?33.25?kcal/mol as determined by MM/PBSA analysis. Importantly, fucoxanthin demonstrated significant immunomodulatory effects by reducing the frequency of key immune cell populations, including CD19⁺ B cells, memory B cells, and activated follicular helper CD4⁺ T (Tfh) cells in cultures of peripheral blood mononuclear cells in vitro. These findings suggest that fucoxanthin acts as a potential IL-21 antagonist, offering a novel therapeutic avenue for autoimmune diseases driven by aberrant B- and T-cell differentiation via the IL-21/IL-21R axis.