Objective To investigate the protective effects of Ziziphus jujuba polysaccharides ( ZJP) on immune suppression and intestinal barrier injury in hindlimb-unloaded (HU) mice. Methods Male ICR mice were divided randomly into six groups: control group, HU group, levamisole group, and ZJP low-, medium-, and highdose groups (ZJP-L, ZJP-M, and ZJP-H groups, 200, 400, and 800 mg / (kg·d)). Mice received the corresponding treatments by oral gavage for 14 consecutive days. Body weight and spleen index were recorded, and histopathological changes in the spleen and colon were examined by hematoxylin-eosin and alcian blue-periodic acid schiff staining. Serum levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-10, immunoglobulin ( Ig) M, and IgG were determined by enzyme-linked immunosorbent assay. mRNA expression levels of inflammation-related genes (Tlr4, Nlrp3, Nos2, Il1b, and Tnf) and barrier-related genes (Tjp1 and Cldn1) in colon tissues were analyzed by real-time quantitative polymerase chain reaction. Results ZJP-L and ZJP-M groups treatment improved the reductions in spleen index compared with HU group (P<0. 05). ZJP-M group markedly reduced IL-1β (48. 15%, P <0. 001) and TNF-α (43. 21%, P<0. 05), while ZJP-L group increased IL-10 by 83. 25% (P<0. 05). The ZJP-L, ZJP-M and ZJP-H groups elevated IgM (22. 54%, 15. 57%, 13. 44%) and IgG (262. 61%, 307. 69%, 230. 58%). All ZJP groups significantly downregulated inflammation-axis genes (Tlr4, Nlrp3, Nos2, Il1b, Tnf) and upregulated barrier-axis genes Tjp1 and Cldn1. Conclusions ZJP markedly alleviates HU-induced immune suppression and intestinal barrier dysfunction, potentially by inhibiting the TLR4 / NLRP3 inflammatory signaling pathway, reducing proinflammatory cytokine production, upregulating tight junction protein-related gene expression, and restoring Ig levels. These findings support the potential application of ZJP in spaceflight immune protection and functional food development.