Inhibition of DPP-4 enzyme actually increases the half life and biological activity of GLP-1 peptide as a result normal glucose level is achieved. Similarly, inhibition of α-glucosidase enzyme suppresses the cleavage of polysaccharides into glucose as a result normal blood glucose index is obtained for the management of diabetes. Sodium–glucose co-transporter 2 (SGLT2) actually reabsorbs the filtered glucose in the tubular nephron of the kidney and thus is the major co-transporter. Fig.1. Mechanism of action and inhibition of DPP-4 enzyme, α-glucosidase and SGLT2. Display omitted •This review article is based on the management of diabetes mellitus which is one of the most challenging diseases of the present time.•DPP-4 enzyme, α-glucosidase enzyme and SGLT2 are effective therapeutic targets for the management of diabetes mellitus.•The identification of promising inhibitors of DPP-4 enzyme, α-glucosidase enzyme and SGLT2 from the natural products are presented.•Structure-activity relationship (SAR) of various inhibitors is also discussed. Diabetes mellitus is a chronic metabolic disorder which is rapidly spreading worldwide. It is characterized by persistent elevated blood glucose level above normal values (hyperglycemia) due to defect in either insulin secretion or in insulin action or both of them. Currently approved oral synthetic antidiabetic drugs such as biguanides, thiazolidinediones, sulfonylureas, and meglitinides have shown undesirable side effects. Therefore, newer approaches and targets for the management of diabetes mellitus are highly desirable. Dipeptidyl peptidase-4 enzyme, α-glucosidase enzyme and sodium-dependent glucose co-transporter 2 (SGLT2) have been recognized as effective therapeutic targets for the management of diabetes mellitus while natural products are alternatives to oral synthetic hypoglycemic agents. During the last two decades, many researchers were working on the identification and the validation of plant-derived products for curing various diseases. Natural products do not only provide useful drugs in their own right but also provide templates for the development of more effective compounds for enhanced therapeutic potential. Herein, we advocated the vital role of natural products as source of new drugs by presenting promising inhibitors of dipeptidyle peptidase-4 enzyme, α-glucosidase enzyme and (SGLT2) obtained from different medicinal plants as potential candidates for drug development against diabetes mellitus. The structure–activity relationship (SAR) of these various inhibitors is also discussed.