Background: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), necessitates effective therapeutic strategies. Polysaccharides derived from Irpex lacteus have demonstrated beneficial biological activities in MRL/lpr mice; however, their precise mechanisms of intervention in LN require further elucidation. Methods: MRL/lpr mice were administered low-dose and high-dose Irpex lacteus polysaccharide (PCP) continuously for 8 weeks. The therapeutic efficacy of PCP was systematically assessed by measuring autoantibody levels, inflammatory cytokine expression, and renal function markers. The underlying pharmacological mechanisms were investigated through integrated transcriptomics and metabolomics analyses. Results: PCP treatment significantly improved renal function in MRL/lpr mice, normalizing serum levels of anti-nuclear antibodies (ANA), anti-double-stranded DNA antibodies (anti-dsDNA), anti-Sm antibody (Sm), creatinine (Cr), blood urea nitrogen (BUN), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and proteinuria. Integrated transcriptomic and metabolomic analyses revealed that the therapeutic action of PCP involves modulation of the PI3K/AKT/NF-κB pathway. This inhibition was further confirmed by Western blot analysis. Conclusions: PCP exerts renal protective effects in MRL/lpr mice by mitigating inflammation, modulating immune responses, and preserving renal function. The combined application of transcriptomics, metabolomics, and Western blotting elucidates that this protection is mediated through inhibition of the PI3K/AKT/NF-κB signaling pathway.