Diabetes mellitus interferes with the metabolism of carbohydrates, causing chronic hyperglycemia. Dyslipidemia in diabetes is a condition that leads to cardiovascular disease. This study was aimed to evaluate the effect of hydroalcoholic Prosopis ruscifolia (Pr) leaves extract on hyperglycemia and lipid profile in normo-and hyperglycemic mice. Mice hyperglycemia was induced by alloxan, animals were treated with Pr (50, 100, 200 mg/kg, p.o., 28 days). Fasted blood glucose level on days 7, 14, 21, and 28 was determined. Blood glucose remained within the normal range in the groups of normoglycemic animals treated with Pr. In the hyperglycemic animals, 100 mg/kg of Pr extract reduced the glycemia, this effect became markedly evident since day 7, until the end of experimental period (p < 0.0001), the total reduction reached was 60%. The lipid profile of normal and hyperglycemic mice was evaluated with 100 mg/kg, on day 28. A non-significant increase in total cholesterol and low density cholesterol, in hyperglycemic animals treated with vehicle, and a statistically significant increase (p < 0.0001) in the level of triglyceride and very low density cholesterol (VLDL) level (p < 0.0001) in normoglycemic animals treated with Pr, compared to the control group were denoted. This could indicate that Pr has a stimulating action on insulin secretion, since hyperinsulinemia is also associated with an increase in the quantity of atherogenic particles of VLDL cholesterol and triglycerides. The coronary risk index and the atherogenic index of hyperglycemic animals treated with Pr showed a reduction compared with the untreated hyperglycemic ones. The presence of three piperidine alkaloids, juliprosopine, 3''''-Oxo-juliprosopine, and julifloridine, previously isolated from P. juliflora, was confirmed. Also, the presence of the flavonoid quercetin was detected in this plant. Those compounds are strong candidates presumably responsible for imparting the effect on glycemia and lipid profile reported here.