Obesity and associated metabolic associated fatty liver diseases (MAFLD) are strongly associated with dysfunction of glucose and lipid metabolism. AMPKα and PPARα are key regulators in the lipid and glucose homeostasis, indicating that novel agents to activate them are promising therapeutic approaches for metabolic syndrome. Noticeably, as a natural anthraquinone derivative extracted from rhubarb, danthron can activate AMPKα in vitro. However, the protective effect of danthron on obesity and associated MAFLD in vivo, as well as the underlying mechanism remains unknown. In this study, obesity and associated MAFLD was induced in C57BL/6J mice by high fat diet (HFD), which were subjected to evaluations on the parameters of systematic metabolism. Simultaneously, the molecular mechanism of danthron on lipid metabolism was investigated in 3T3-L1-derived adipocytes and HepG2 cells in vitro. In vivo, danthron significantly attenuated the obesity and MAFLD by enhancing hepatic fatty acid oxidation, decreasing lipid synthesis, and promoting mitochondrial homeostasis. Mechanistically, danthron significantly promoted combination of RXRα and PPARα, enhanced the binding of RXRα/PPARα heterodimer to the promoter of adiponectin receptor 2 (AdipoR2), by which activating the AMPKα and PPARα pathway. Moreover, PPARα and AdipoR2 can interplay in a loop style. Collectively, this study demonstrates that danthron can substantially ameliorate obesity and associated hepatic steatosis via AdipoR2-mediated dual PPARα/AMPKα activation, which suggests that danthron might be a novel therapeutic approach for inhibition of obesity and hepatic steatosis.