Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (<b>1</b>) exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7-prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound <b>10</b> and chrysin 5,7-diprenylether compound <b>11</b>, with the improved pharmacological profile compared with chrysin (<b>1</b>). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds <b>10</b> and <b>11</b> functioned as peroxisome proliferator-activated receptor (PPAR)γ partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound <b>11</b> showed PPARγ binding affinity as potent as that of the PPARγ agonists pioglitazone and telmisartan. This study presents a novel PPARγ partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.