Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized for its global prevalence and potential progression to more severe liver diseases such as non-alcoholic steatohepatitis (NASH). The primary treatment for NASH is modifying lifestyle through dietary or exercise interventions. The aim of the current study is to investigate the roles of Fufang Zhenzhu Tiaozhi polysaccharides (FTZPs) in mice with NASH. FTZPs were concurrently administered to high-fat diet (HFD)-induced 24-week NASH model mice. FTZPs treatment effectively improved liver lipid metabolism, reduced inflammation and fibrosis, improved the integrity of the intestinal mucosal barrier, and modulated the structure of the intestinal microbiota. FTZPs treatment significantly reduced the abundance of Gammaproteobacteria, Clostridium, and Coprococcus while as induced the abundance of Dehalobacteraceae and Dehalobacterium. Furthermore, sixteen differential metabolites were screened by metabolomics, and the change of asparagine was the most significant. In addition, the correlation analysis showed that there was a significant correlation between asparagine and the aforementioned differential bacteria. The present study demonstrated that FTZPs, as the fundamental pharmacological elements of FTZ (Fufang Zhenzhu Tiaozhi), protect against NASH by improving intestinal barrier damage and regulating intestinal flora with the increase in asparagine.