Obesity is an increasingly concerning global health issue, which is accompanied by disruption of glucose and lipid metabolisms. The aim of this study was to uncover the potential and molecular actions of puerarin, a phytochemical, for alleviating metabolic dysfunctions of glucose and lipid metabolisms. A rat model fed a high fat and high fructose diet and a HepG2 cell model challenged with fructose combined with free fatty acid were utilized to identify the effects of puerarin on obesity-associated insulin resistance and hepatic steatosis. The molecular mechanisms underlying puerarin treatment effects were further investigated using qRT-PCR and western blotting. Results show that puerarin significantly ameliorated features of obesity in rats, including bodyweight, hyperlipidemia, hyperglycemia, glucose/insulin intolerance, insulin resistance, hepatic steatosis, and oxidative stress, which are related to the activation of AMPK and PI3K/Akt pathways in the liver. Puerarin reduced lipid accumulation and caused a reduction of the mRNA expression of lipogenic genes such as SREBP-1c, FAS, SCD-1, and HMGCR, and an increment in the phosphorylation of AMPK and ACC in HepG2 cells. Moreover, puerarin ameliorated insulin resistance by increasing GLUT4 mRNA expression and activating the PI3K/Akt pathway. Treatment with the AMPK inhibitor compound C partially abolished the beneficial effects of puerarin on lipid accumulation and insulin resistance in HepG2 cells, which indicated that the protective effects of puerarin partially depend on the AMPK pathway. The present study indicates that puerarin shows potential as a functional food therapeutic for the treatment of obesity.