We previously showed that Aster spathulifolius Maxim extract (ASE) reduced body weight gain and serum and liver lipid levels and significantly suppressed serum insulin and leptin concentrations in high-fat diet (HFD)-induced obese rats. Germacrone (GM) was identified as a potent bioactive constituent of ASE. In this study, we hypothesized that GM can attenuate hyperlipidemia by alleviating fatty acid (FA) synthesis/uptake and improve lipid metabolism by stimulating FA β-oxidation in HFD-induced obese C57BL/6J mice. To induce obesity, mice were fed an HFD for 6 weeks, while control mice were fed a commercial standard diet. The mice were allocated to six groups and fed either a normal diet, HFD, HFD with GM (5, 10, and 20 mg/kg), or HFD with 200 mg/kg Garcinia cambogia extract for 30 days. In the GM groups, body weight gain, visceral fat pad weight, fasting plasma glucose, serum insulin and leptin, and serum, as well as hepatic lipid, levels were attenuated. Transcriptional factors related to lipid metabolism, such as AMP-activated protein kinase α, sterol regulatory element-binding protein (SREBP) 1, SREBP 2, acetyl-CoA carboxylase, peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, FA synthase, and carnitine palmitoyltransferase 1, showed higher expression in the GM groups. In summary, GM may help attenuate hyperlipidemia by suppressing FA synthesis and uptake by inhibiting SREBP signaling pathway activation and improve lipid metabolism by stimulating FA β-oxidation by activating the AMPKα signaling pathway in HFD-induced obesity.