Diet-induced obesity (DIO) is commonly associated with hyperleptinemia and leptin resistance. Leptin acts centrally to inhibit food intake and increase energy expenditure, thereby preventing body weight gain. Resistance to the biological effects of leptin represents a major obstacle in utilizing exogenously administered leptin as a treatment option for obesity. Of importance, recent studies demonstrate that naturally occurring compounds improve leptin sensitivity in DIO mice, as revealed by anorectic and body weight-lowering effects. To date, the role of sulforaphane (SFN, an isothiocyanate derived from cruciferous vegetables) on leptin responsiveness has not been examined, in spite of its known beneficial effects toward lowering body weight gain in DIO. In the present study, we determined the extent to which SFN regulates leptin responsiveness in high-fat high-sucrose (HFHS) diet-fed obese mice. SFN treatment (0.5 mg/kg/day, s.c.) for 23 days in HFHS-fed mice improved the responsiveness to intraperitoneally-injected leptin by promoting significant decreases in cumulative food intake and body weight gain. A single leptin injection (2 mg/kg; i.p.) resulted in significant decreases in food intake at 24 h and 38 h time points. In addition, a triple leptin injection (1 mg/kg/day, 3 days; i.p.) led to significant decreases in food intake at 14 h, 24 h, 38 h, 48 h, and 62 h time points. Furthermore, single and triple leptin injections prevented body weight gain at 38 h and 62 h time points, respectively. The present findings suggest that intervention with SFN, a naturally occurring isothiocyanate, has the potential to improve leptin responsiveness in DIO.