Cardiovascular complications and associated conditions remain a major cause of death, globally. Piliostigma thonningii has been used for different and several medicinal purposes. On this background, the effect of aqueous leaf extract of the plant on the lipid profile of physiologically normal rats was examined. Graded doses of the extract, 0.0, 0.2, and 0.4 g/kg of body weight (bwt) were orally administered to rats for a period of 14 days. The effect of the extract was assessed on the basis of comparative determinations of the evaluated indices in treated rats vis-à-vis the nontreated group as well as in respect to the differences between the basal and final concentrations of the indices in each group. The extract, especially at 0.2 g per kg body weight caused a significant decrease in the total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol in the treated rats when compared to the control group and basal concentrations. Though, the level of high-density lipoprotein (HDL) cholesterol increased in the treated rats, the increase was not significant when compared to the basal concentration. The LDL/HDL ratio in all the experimental groups was less than 0.9. The results obtained in this study suggest that P. thonningii aqueous leaf extract likely contains antilipidaemic and anticholesterolaemic substance(s), which may be useful in the prophylactic and curative management of lipid peroxidation, high blood pressure, and cardiovascular disorders.