Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic manifestation of metabolic dysfunction for which effective interventions are lacking. The burden of NAFLD is increasing at an alarming rate. NAFLD is frequently associated with morbidities such as dyslipidemia, type 2 diabetes mellitus and obesity, etc. The current study explored the potential role of bound polyphenols from foxtail millet (BPIS) in treating mice with NAFLD induced by a high-fat diet (HFD). The results indicated the critical role of BPIS in treating NAFLD by effectively restoring the gut microbiota in C57BL/6 mice that received a high-fat diet (HFD) for 12 weeks. At the same time, 16S rRNA analysis demonstrated that BPIS remodeled the overall structure of the gut microbiota from fatty liver diseases towards that of normal counterparts, including ten phylum and twenty genus levels. Further study found that the expression of tight junction proteins was upregulated in the BPIS-treated group. This study provides new insights into the potential NAFLD protective effects induced by polyphenols of foxtail millet.