Elevated blood sugar levels and a plethora of other, more diverse diseases, including changes to protein, carbohydrate, and lipid metabolism, are the only hallmarks of diabetes mellitus. Recent research has shown that mice lacking PTP1B had better glucose tolerance, less diet-induced obesity, and insulin sensitivity in general. In the therapy of serious diabetic problems, natural chalcones have recently been discovered, which have superior selectivity and do not affect pharmacokinetics. This is in response to the present demand for improved PTP-1B inhibitors. No appropriate formulation has been developed for the inhibitors based on natural products chalcones as they have not been tested clinically for toxicological characteristics. The review article has extensively covered various unknown natural chalcone compounds, such as kuwanon J, kuwanon R, kuwanon V, isoliquiritigenin, xanthoangelol, xanthoangelol D, xanthoangelol E, xanthoangelolF, xanthoangelol K, 4-hydroxyderricin, 5,4__ampersandsignrsquo;-dihydroxy-6,7-furanbavachalcone, licochalcone A, licochalcone B, licochalcone C, licochalcone D, licochalcone E, echinatin, laxichalcone, broussochalcone, macdentichalcone, (2E)1, 1-(5,7-dihydroxy-2,2-dimethyl-2H-benzopyran-8-yl)}3-phenyl-2-propen-1-one, often known as 2E(abyssinone-VI-4-O-methyl ether, 1-(5,7-dihydroxy-2,2,6-trimethyl-2H-benzopyran-8-yl)-3-(4-methoxyphenyl)-2-propen-1-one) show great promise as a diabetic medication because it can inhibit insulin degradation by targeting the therapeutic target protein tyrosine phosphatase 1B (PTP-1B). These chalcone-based PTP-1B inhibitors derived from natural products are not currently used in clinical trials and have not attracted much interest from contemporary medicine due to a lack of clinical investigation into their toxicological profiles necessary to create an appropriate formulation. These chalcone-based PTP-1B inhibitors may soon unlock new opportunities in diabetotherapeutics.