The nutritional transition in sub-Saharan Africa, marked by increased consumption of energy-dense foods, has contributed to the rising prevalence of type 2 diabetes. Oxidative stress plays a central role in insulin resistance and glucose intolerance. The validation of traditional medicinal plants such as Elephantopus mollis (Asteraceae) may provide alternative therapeutic strategies. Elephantopus mollis is used in Cameroon eastern region folk medicine in the management of diabetes and obesity. This study aimed to evaluate the phytochemical profile, in vitro antioxidant activity, and the effect of E. mollis aqueous extract on glycaemia reactivity and anthropometrics parameters on MACAPOS 2 high-fat diet fed rats. Total phenolic, flavonoids, tannins, alkaloids and saponins contents of extract were determined using standard methods. The Antioxidant potential was explored considering 1.1-Diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, nitric oxide radical inhibiting activity, Ferric Reducing Antioxidant Power (FRAP) ability, and total antioxidant capacity of the extract. Thirty-six male Wistar rats were fed a standard or high-fat diet for 30 days and treated concomitantly with once daily oral administration of E. mollis aqueous extract (Em50, 100 and 200 mg/kg b.w.) or metformin (70 mg/kg b.w.). The effect of E. mollis were investigated on, fasting glycaemia, glucose tolerance, insulin sensitivity, body weight gain, white adipose tissues (visceral, perirenal and peritesticular fats), food and water intakes. In Elephantopus mollis aqueous extract, saponins were the most abundant quantified metabolites (907.5 ± 18.37 µg SE/g), followed respectively by total polyphenols (788.67 ± 11.58 µg GAE/g), flavonoids (189.02 ± 7.96 µg QE/g), alkaloids (108,52 ± 9,75 µg QiE/g) and tannins (5,25 ± 0,18 µg TAE/g). This extract showed strong antioxidant activity by inhibiting nitric oxide, scavenging DPPH free radicals, reducing power. The MACAPOS 2 high-fat diet increased fasting glycemia, induced glucose tolerance, insulin resistance, and fat accumulation. The E. mollis extract decreased fasting glycemia, body weight gain, food and water intake. This extract remarkably (p < 0.01) decreased white adipose tissues associated with a significant improvement of glucose tolerance, and peripheral insulin sensitivity. E. mollis aqueous extract exhibited significant antioxidant potential, decreased fasting glycemia, improved glucose tolerance, insulin sensitivity and anthropometric parameters thus justifying its empirical use in the management of diabetes and obesity.