Background: Radix Astragali is an herb with tonifying qi or adaptogenic effects and commonly used for spleen-qi deficiency in traditional Chinese medicine. Astragalus polysaccharides (APS) is one of the major bioactive ingredients, and little is known on APS in attenuating the dampness stagnancy due to spleen deficiency (DSSD). Objective: The objective of the study is to investigate the potential mechanism of action of APS underlying attenuating water and fluid retention of rats with the DSSD syndrome in order to provide novel insights into the application of APS on modulating the DSSD syndrome. Materials and Methods: Four-week-old Wistar rats were fed with one high-fat and low-protein diet and subjected to exhaustive swimming to induce the DSSD model for 8 weeks. APS (300, 600, and 1200 mg/kg) and Shen Ling Bai Zhu San (SLBZS) (2.5 g/kg) were administrated starting at 9 weeks for 2 weeks. Results: APS increased the body weight, decreased the water load index, and attenuated symptoms of the DSSD syndrome. APS also increased spleen and thymus indices, the percentage of CD3+, the percentage of CD3+ CD4+, and CD3+ CD4+ to CD3+ CD8+ ratio and decreased levels of serum interleukin (IL)-6, IL-10, and tumor necrosis factor-α in DSSD rats. Significant effects were seen for toll-like receptor 4 (TLR4) at both protein and gene expression levels with amelioration of expression levels in APS groups. Conclusion: These findings suggest that APS may be used to attenuate the fluid retention of the DSSD syndrome through the immunoregulatory effect, which is driven in part by the modulation of TLR4.