Objective: This study aimed to test the hypothesis that Hibiscus sabdariffa Linn. Extract (HSE) would increase arcuate nucleus Lep-R, NPY, and white adipose tissue β3AR mRNA expression in DIO rats. This study also analyzed the potency of H. sabdariffa bioactive compounds as an activator of Lep-R and β3AR. Methods: Twenty-four male Sprague-Dawley rats were separated into four groups: Control (standard chow), DIO (HFD), DIO-Hib200 (HFD+HSE 200 mg/kg BW), and DIO-Hib400 (HFD+HSE400 mg/kg BW). HSE administration was administered orally for five weeks, once a day. Result: The administration of HSE significantly (P<0,05) increased the arcuate nucleus Lep-R expression, but not for the ARC NPY and WAT β3AR. The Lee index of DIO rats also significantly decrease (p<0,001 for a dose of 200 mg/kg BW and p<0,01 for a dose of 400 mg/kg BW) into the normal range (≤ 310). Among 39 bioactive compounds, 5-O-caffeoylshikimic acid has high free binding scores (-8,63) for Lep-R, and myricetin_3_arabinogalactoside has high free binding scores (-9,39) for β3AR. These binding predictions can activate Lep-R and β3AR. Conclusion: HSE increases leptin sensitivity and reduces obesity, and its bioactive compounds can activate the Lep-R and β3AR to regulate energy balance. HSE could be a potential therapeutic target for obesity.