Phosphorylated modification of plant polysaccharides has emerged as an effective strategy to enhance their bioactivity. Here, we compared phosphorylated Scrophularia ningpoensis polysaccharides (PSNPs) with the native form (SNPs) in a cyclophosphamide (Cyp)-induced immunosuppression mouse model. In vitro, both SNPs and PSNPs scavenged hydroxyl and ABTS radicals in a dose-dependent manner, with PSNPs showing superior hydroxyl radical scavenging above 0.5?mg/mL. In vivo, Cyp administration markedly decreased superoxide dismutase (SOD) activity and increased malondialdehyde (MDA) levels in liver and serum, indicative of oxidative stress. Both SNPs and PSNPs significantly restored SOD activity and reduced MDA levels, with PSNPs showing greater efficacy. Immunohistochemical analysis further revealed that Cyp-induced suppression of hepatic nuclear factor erythroid 2–related factor 2 (Nrf2) expression was effectively reversed by SNPs and more prominently by PSNPs. Immune function assessment revealed that Cyp-induced thymus and spleen atrophy was significantly reversed by SNPs or PSNPs, with PSNPs producing a more pronounced recovery. Cytokine profiling showed that both treatments elevated the anti-inflammatory cytokine IL-10 and reduced the proinflammatory cytokines TNF-α and IL-6, with PSNPs achieving stronger modulation. Immunohistochemistry confirmed nuclear factor-kappa B (NF-κB) activation in ear tissue was markedly reduced, especially by PSNPs. Furthermore, 16S rRNA sequencing demonstrated that SNPs and PSNPs reshaped the gut microbiota by enriching beneficial genera and suppressing pathogenic taxa, with PSNPs inducing greater microbiota remodeling. These findings indicate PSNPs exert enhanced antioxidant, immunomodulatory, and gut microbiota–modulating activities, likely via coordinated Nrf2 activation, NF-κB inhibition, and microbial community regulation, highlighting their potential against chemotherapy-induced immunosuppression and oxidative injury.