Citrinin (Cit) is a metabolite of Monascus Aspergillus that is known to be nephrotoxic and affects the safety of Monascus products. Here, we investigated the effects of an intervention with bioactive Polygonatum sibiricum polysaccharides (PSPS) on Cit-induced toxic damage in populations with dietary patterns characterized by alcohol consumption. Our results showed that the PSPS intervention significantly increased the levels of intestinal Cit and its metabolite M1. Additionally, the PSPS intervention mitigated intestinal damage, as well as liver and kidney stress, and flora disruption induced by combined exposure to Cit and alcohol. It also promoted the recovery of Lactobacillus abundance. However, there was no significant improvement in hippocampal damage. Metabolomics analysis indicated that the PSPS significantly influenced the metabolic pathways involved in energy metabolism in liver and kidney, such as aspartic acid and tyrosine metabolism. Correlation analysis revealed a significant relationship between the reduction of Cit metabolites and the differential metabolites in the liver and kidney. Our results demonstrated that the PSPS intervention showed promise in improving intestinal flora imbalances, enhancing the barrier function against Cit, alleviating intestinal, liver, and kidney damage, and addressing the metabolic disorders along the gut-liver-kidney axis resulting from the co-exposure to Cit and alcohol.