Intestinal barrier damage is frequently caused by antibiotic therapy, potentially leading to bacterial translocation and toxin leakage, which triggers inflammation and increases the risk of various diseases. In this study, Tamarind seed polysaccharides (TSP) with different molecular weights were administered to mice during the recovery phase from clindamycin-induced intestinal barrier damage. The results indicated that TSP restored the shortened colon length, reduced the enlarged cecum index, and decreased the elevated level of inflammatory infiltration. Biochemical testing revealed that TSP decreased the levels of intestinal permeability biomarkers and inflammatory factors that were elevated by clindamycin treatment. Transcriptomics and non-targeted metabolomics analyses respectively uncovered changes in colon gene expression and fecal metabolites. The joint analysis of these omics data identified critical pathways, including arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings suggest that TSP could be a promising dietary supplement for protecting the intestinal barrier and alleviating inflammation.