Abstract: Objective: To investigate the effects of Panax quinquefolius polysaccharides on intestinal side effects induced by antibiotics (clindamycin phosphate), including diarrhea, intestinal structural integrity, composition and diversity of gut microbiota. Methods: After water extraction, alcohol precipitation and deproteinization, the water-soluble Panax quinquefolius polysaccharide (WQP) was obtained from the root of Panax quinquefolius. The model of antibiotic-related side effects was established by intragastric administration of clindamycin phosphate, and then intervened with normal saline (natural recovery group, NR) or WQP group. Results: The results showed that WQP was mainly composed of galacturonic acid, glucose, galactose and arabinose. The yield, total sugar content, uronic acid content and protein content were 6.71%, 85.2%, 31.9% and 2.1%, respectively. The results of pharmacological experiments showed that WQP could relieve diarrhea symptoms, improve colonic edema, increase the length of intestinal villi and restore the diversity of gut microbiota. Compared with NR group, WQP decreased the relative abundance of Firmicutes and Proteobacteria in gut microbiota and increased the relative abundance of Bacteroidetes in gut microbiota, while WQP decreased the relative abundance of Bacteroides and Clostridium at genus level. Conclusion: WQP can improve the richness and diversity of gut microbiota by promoting the repair of intestinal structure in rats, and then alleviate the antibiotic-related side effects such as diarrhea and flora imbalance caused by clindamycin phosphate.