Abstract: Objective: This study constructed a high-fat diet (HFD)-induced obesity mouse model and evaluated the effect of Physalis alkekengi L. fruit polysaccharides (PFP) on preventing high-fat diet-induced glucose and lipid metabolism disorders in mice. Methods: Twenty-eight 6-week-old male C57BL/6 mice were randomly assigned to four groups: blank control (CON), model (HFD), low-dose PFP administration (50 mg/kg, PFPL), and high-dose PFP administration (100 mg/kg, PFPH), with seven mice per group. The mice received daily gavage for 12 weeks, during which their body weights were measured weekly. Fecal, serum, and tissue samples were collected 24 hours after the final gavage. Serum biochemical indicators, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activity were analyzed. Serum and liver levels of TNF-α, IL-1β, and IL-6 inflammatory factors were quantified using ELISA. The expression levels of liver glucose and lipid metabolism related genes, intestinal inflammatory factors and permeability related genes (ZO-1, Occludin, and Claudin-1) were measured using RT-qPCR. Additionally, gas chromatography mass spectrometry detection was conducted to determine the short-chain fatty acids (SCFAs) concentration in the intestine. Results: Compared to the HFD group mice, the PFP-administered mice efficiently inhibited the rapid increase in body weight and reduced the liver index. They also, to varying degrees, lowered the fasting blood glucose levels and significantly decreased insulin levels and the insulin resistance index (P<0.05). The PFPH group mice showed a significant reduction in serum TC, TG, and LDL-C levels (P<0.001). RT-qPCR results indicated that PFP supplementation regulated the expression of genes associated with glucose and lipid metabolism in the mouse liver. Additionally, PFP administration reduced the levels of pro-inflammatory factors TNF-α, IL-6, and IL-1β in both serum and liver, effectively lowering serum MDA levels and increasing SOD activity. PFP supplementation also significantly enhanced the expression levels of ZO-1, Occludin, and Claudin-1 in the mouse colon tissue (P<0.05). Furthermore, the PFPH group mice showed a significantly increased content of SCFAs, particularly butyric acid, in the intestines of mice (P<0.05). Conclusion: PFP administration effectively regulated the high-fat diet-induced disturbances in glucose and lipid metabolism. It improved insulin resistance, enhanced the antioxidant capacity of the body, reduced inflammation, increased the expression of genes related to intestinal permeability, and increased the SCFAs content in the intestine. Collectively, these effects exerted protective effects against metabolic disorders induced by high-fat diet in mice.