Pharmacokinetic studies of traditional Chinese medicine polysaccharides (TCMPs) are essential for elucidating the material basis of their pharmacological effects. A central challenge in this field lies in the paradox between their low oral bioavailability and significant systemic efficacy. Research has demonstrated that TCMPs exhibit low plasma concentrations following oral administration, and their therapeutic effects are largely independent of direct prototype absorption, instead being mediated through indirect mechanisms such as gut microbiota-derived metabolites and immunomodulation. In terms of distribution, TCMPs selectively target organs rich in mononuclear phagocytes, such as the liver and spleen, where they engage pattern recognition receptors to initiate immune regulation. Their metabolism involves a synergistic action between host enzymes and gut microbiota, with fecal excretion serving as the primary elimination route. A groundbreaking study by Ding et al. has recently provided direct evidence that specific structural types of TCMPs, such as 1, 3- and 1, 4-linked glucans, can be absorbed as intact macromolecules via a clathrin/dynamin-1/Rab5-mediated endocytic pathway, offering a mechanistic explanation for their systemic efficacy. Current research continues to face challenges, including insufficient sensitivity of analytical methods and the complexity of metabolic networks. Future integration of highly sensitive analytical techniques, multi-omics approaches, and artificial intelligence will drive the field toward more precise and systematic investigation, facilitating the clinical translation of TCMPs.