The therapeutic effect of polysaccharide of large yellow croaker swim bladder (PLYCSB) on lupus nephritis has been studied in vivo. A high concentration (50 mg/kg dose) of PLYCSB reduced the levels of serum inflammatory cytokine levels of IL-6, IL-12, TNF-α and IFN-γ compared to a low concentration (25 mg/kg dose) and control mice. SCr, BUN, TC and TG serum levels of PLYCSB treated mice were lower than those of control mice, and TP and ALB serum levels were higher than control mice. Control mice tested ds-DNA positive at the 6th week, and 50 mg/kg treated mice tested at the 10th week after the experiment began. The output of urine protein of 50 mg/kg PLYCSB treated mice was most closely comparable to the normal mice. The glomerular number of 50 mg/kg PLYCSB treated mice was more than the 25 mg/kg dose and control groups, and the 50 mg/kg dose group showed the lowest glomerular sclerosis index in lupus nephritis mice. By RT-PCR and western blot assay, PLYCSB significantly induced inflammation in kidney tissues of mice by downregulating NF-κB-p65, TGF-β1, Fas, FasL and upregulating IκB-α. These results suggest that PLYCSB showed a potential curative effect on lupus nephritis as a drug or functional food.