Diabetes mellitus has been observed to be amongst the main manifestation of the metabolic syndrome with rising global incidence and prevalence all over the globe. Type II diabetes has been demonstrated as the cause of morbidity and mortality mainly due to enhanced risk of certain cardiovascular disorders (CVDs) that has contributed a huge disease burden on the humankind. In addition, hypertension, hyperlipidemia and endothelial dysfunctions have been reported as the major pathologies of prevailing CVDs imposing greater risks to human health. Multiple synthetic agents are currently available for the management of diabetes and its associated CVDs. However, lifelong use of these drugs has been found to be coupled with many adverse effects that result in patient unaffordability and non-compliance. Fortunately, Pakistan has rich medicinal flora and its people prefer using herbal remedies for the treatment of various chronic ailments including diabetes and CVDs. In local traditional medicine, a polyherbal formulation (POL-4) has been prescribed. It has been reported to contain a mixture of four herbs namely; the powdered seeds of Nigella sativa (Ns.Cr), Cichorium intybus (Ci.Cr), Trigonella foenum graecum (Tfg. Cr) and leaves of Gymnema sylvestre (Gs.Cr) in equal amounts. A few reports are available in the literature showing effectiveness of its individual plant drugs, but no detailed scientific study was available to show antidiabetic and/or cardiovascular efficacy of POL-4. Therefore, the present investigation was designed to determine the efficacy and mechanism of action of POL-4aswellasthatofitsingredientsindiabeticanimalmodelsandtheassociatedCVDs. Phytochemical assays were conducted qualitative analysis of constituents present in the extract of POL-4 and its individual plants which have been already reported to contain many active constituents(alkaloids, saponins, tannins, flavonoids, anthraquinones, coumarins and terpenoids). In addition, quantitative analysis of total flavonoid and phenolic contents were also carried out, these entities have been found in much quantities in POL-4 and its constituent plants and have been reported to possess antioxidant and radical scavenging properties, which are considered essential for promoting long life and risk reduction. These extracts or powdered POL-4 and its individual ingredients were studied for antihyperglycemic, antihyperlipidemic, antihypertensive and endothelial modulating properties using different in vivo and in vitro models. The oral administration of POL-4 to glucose preloaded in rats in oral glucose tolerance test (OGTT) produced a marked decrease inbloodglucoselevelatvarious timeintervalsandeffect was foundsimilartoglibenclamide. Further, administration of POL-4 to alloxan-induced and fructose-fed diabetic rats prevented the rise in fasting blood glucose (FBG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) but raised the high density lipoprotein-cholesterol (HDL) levels. It was also found to produce improvement in endothelial dysfunction and associated hypertension. Histomorphometric findings of the treated rats (alloxan and fructose models) showed improvement in the morphology of islet of Langerhans. Further experiments in anesthetized rats, intravenous administration of extracts of POL-4 and its ingredients caused a dose-dependent fall in mean arterial pressure, comparable to verapamil. When tested on pre-contracted isolated rat aortic preparations, these extracts caused inhibition of high K+(80 mM)-induced contractions in such an order Ci.Cr>Ns.Cr>Tfg.Cr>Gs.Cr≅POL-4. However, on phenylephrine-induced contractions, Ci.Cr and Tfg.Cr showed complete relaxationwhilePOL-4.Cr,Gs.Crand Ns.Crshowed dualvasoconstriction andvasodilatation effects. To confirm Ca++ antagonist-like activity, the POL-4 and its ingredients produced positive results similar to verapamil. In addition, on the basal tone of aortic preparations, parent formulation and its ingredients except Tfg.Cr produced partially phentolamine (µM)-sensitive vasoconstriction. In isolated guinea-pig atria, the POL-4 and its three constituents (C. intybus, G. sylvestre and T. foenum graecum) fully decreased the force and rate of spontaneously beating atria, similar to verapamil. Then POL-4 and its ingredients were mixed with high fat-diet (HFD)- fed rats caused marked attenuation of serum TC , LDL-C , FBG, atherogenic index, coronary risk index and c-reactive proteins, while an increasewas notedinHDL-C and TGlevels,similarthatproduced byatorvastatin. ThePOL 4 and its ingredients reduced the systolic blood pressure of rats and significantly improved theendothelial dysfunction by augmenting acetylcholine-mediated relaxation. The extracts of POL-4 and its ingredients were administered to BALB/c mice in increasing serial doses (1, 3 and5g/kgbodywt.orally) wereunabletocauseanytoxicsymptomsormortality. In conclusion, it is conceivable from these data, POL-4 has been found to possess phytochemical constituents which possess marked antihyperglycemic and antihyperlipidemic effects probably by inhibition of reactive oxygen species. The formulation and its ingredients possessed hypotensive effect predominantly mediated through blocking the calcium influx through membranous calcium channels and receptor operated (α-adrenergic receptor) pathways. The antihyperlipidemic effect of POL-4 and its ingredients may be attributed to absorption of lipids. Histomorphological finding of pancreatic tissues showed evidence of improvement. Acute toxicity studies showed safety of the formulation of tested doses. Thus the observed antihyperglycemic, antihyperlipidemic, antihypertensive and endothelial modulating properties of POL-4 and its ingredients provide validation of the empirical use of thePOL-4inthetraditionalmedicineforthetreatmentofdiabetesandtheassociatedCVDs.