Pathway analysis highlighted effects on fatty acid metabolism, PPAR signaling, and NAFLD-related pathways.<h4>Conclusion</h4>Our study provides a comprehensive multi-omics analysis revealing that semaglutide modulates serum proteomic and metabolomic profiles in T2DM-MAFLD patients, potentially through enhancing mitochondrial β-oxidation, reducing lipid toxicity, and suppressing inflammation. This evidence concerns the gene PPARA and type 2 diabetes mellitus.