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Obesity is associated with an increased risk of chronic diseases and affects the overall quality of life. Gardenia jasminoides (Ellis) fruit (GE) and Eucommia ulmoides leaves (EE) are traditional medicines reported to possess antioxidative, anti-hyperglycemic, anti-hyperlipidemic, and anti-obesity activities. However, the synergistic effect of combining Gardenia and Eucommia remains unclear. This study aimed to test the combination via animal and cell experiments. GE extract mainly contains geniposide (52.5 %), whereas EE extract contains crocin (10.5 %) and chlorogenic acid (52.3 %). Copper soap analysis revealed that the combination of GE and EE induced greater pancreatic lipase activity. In C57BL/6J mice, this combination markedly improved hypertriglyceridemia and hyperglycemia in intravenous fat and intraperitoneal glucose tolerance tests, respectively. In HepG2 cells with hyperlipidemia induced via oleic acid (OA), GE + EE reduced the accumulation of ectopic lipid and augmented the oxidative stress-related enzyme activities by elevating PPARα, AMPK, Nrf2, and HO-1 expression and attenuating Keap-1 expression. Thus, this combination protects against OA-induced lipid toxicity by targeting AMPK-PPARα and Nrf2- Keap-1-HO-1.