Background: We have shown Sclerocarya birrea fruit peels to possess in vitro antioxidant activity but yet to demonstrate its medicinal potential in vivo. Objectives: To investigate the effect of S. birrea fruit peel on diet-induced obesity and metabolic syndrome (MetS) in female Wistar rats. Materials and Methods: S. birrea fruit peels extract was profiled for phytochemicals by liquid chromatography-mass spectrometer. Total polyphenols, flavonoid, and total antioxidant capacity was determined by the colorimetric methods. Four groups of female rats (n = 6/group) were administered high energy diet (HED) formulation for 15 weeks then treated daily for 4 weeks as follows: normal diet and HED control groups received distilled water; HED treated with S. birrea hydroethanolic (70% ethanol) extract at 100 mg/kg BW (HED 100) and 200 mg/kg BW (HED200). Fasting glucose and body weights were monitored weekly. Oral glucose tolerance test and blood pressure (BP) were measured before and after treatment. After termination, visceral fat, total liver fat, lipid profiles, adiponectin, leptin, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. Results: S. birrea fruit peel was rich in polyphenols and had higher antioxidants activity than the fruit pulp. Untreated HED-fed rats showed increased body weight gain, visceral fat deposition, increased total cholesterol, glucose tolerance, serum insulin and HOMA-IR, increased BP and inflammation (increased serum leptin, leptin: adiponectin ratio and reduced adiponectin) as compared to normal control. Treatment with S. birrea extract at both doses fully or partially stabilized all these parameters except BP, triglycerides and low-density lipoprotein cholesterol which remained elevated after the 4-week treatment period. Histological examination showed reduced hepatic steatosis, thereby reducing non-alcoholic fatty liver disease. Conclusion: S. birrea fruit peel extract ameliorated obesity and MetS by reversing diet-induced visceral fat accumulation, hepatosteatosis, hypercholesterolemia, improving insulin resistance and inflammation and stabilizing leptin: adiponectin balance.