Soybean dregs are one of the most important albeit underutilized byproducts in soybean processing. In this study, soluble soybean polysaccharides with lipid-lowering activity were extracted from soybean dregs and used as a wall material for embedding metformin. Metformin-soluble soybean polysaccharide nanoparticles (MET-SSPS-NPs) were prepared by electrostatic interaction. The lipid-lowering activity and possible mechanism of MET-SSPS-NPs were investigated. Western blotting was used to detect the expression levels of cell-related protein proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) in vitro. The results showed that MET-SSPS-NPs lowered the expression of PCSK9 and improved LDLR levels. A high-fat diet (HFD) animal model was established to study the lipid-lowering effect of MET-SSPS-NPs by real-time quantitative PCR and western blotting. MET-SSPS-NPs significantly upregulated peroxisome proliferator-activated receptor gamma (PPARγ) expression and downregulated PCSK9, fatty acid-binding protein (FABP) 7 and FABP5 expression more strongly than MET or SSPS alone. In conclusion, MET-SSPS-NPs can inhibit PCSK9 expression and improve the level of adipokines, providing a theoretical basis for the application of MET-SSPS-NPs in lipid lowering. © The Royal Society of Chemistry 2022.