Objective To investigate the effects of aerobic exercise combined with paeonol poly(lactic-coglycolic) acid (PLGA) nanoparticles on blood biochemistry and lipid metabolism in obese rats with hyperlipidemia. Methods Male Sprague-Dawley rats were fed a high-fat diet to induce a model of obesity with hyperlipidemia. Model rats were randomly divided into the model control group, aerobic exercise group, paeonol PLGA nanoparticle group, and aerobic exercise combined with paeonol PLGA nanoparticle group (SP), with 8 rats per group. The intervention was continuous, and the body weights were measured weekly for 6 weeks. After the intervention, total cholesterol, triglycerides and highdensity lipoprotein were assayed using an automatic blood biochemistry analyzer, and then the liver coefficient was calculated. The serum lipoproteinase and hepatic lipase contents were detected, and the abdominal fat was sampled for pathological examination. Results The body weight, blood biochemical parameters, liver coefficient, lipoproteinase and hepatic lipase contents of the aerobic exercise group, paeonol PLGA nanoparticle group and SP groups were improved, compared with those of the model control group. The SP group was improved the most compared with the model control group, and the result were statistically significant ( P <0. 01). The result of the abdominal fat pathology for the same field of view showed that the SP group mice had the most small and numerous abdominal fat cells. Conclusions Aerobic exercise combined with paeonol PLGA nanoparticles can ameriortae the obeisity-acompanying high-fat diet-induced lipid metabolic disorder, reduce the liver indices, regulate lipid metabolism and alleviate fat accumulation in rats.