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The global prevalence of diabetes mellitus is rising, especially in India. Medicinal herbs, whether used alone or in combination with conventional medicines, have shown promise in managing diabetes and improving overall well-being. Piperine (PIP), a major bioactive compound found in pepper, is gaining attention for its beneficial properties. This study aimed to assess whether PIP could alleviate diabetes by targeting insulin pathway-related molecules in the adipose tissue of rats on a high-fat diet (HFD). After 60 days on the HFD, rats received PIP at a dose of 40 mg/kg body weight for one month. The results showed that PIP significantly improved metabolic indicators, antioxidant enzymes, and carbohydrate metabolic enzymes. It also regulated the mRNA and protein expression of insulin signaling, which had been disrupted by the diet and sucrose intake. Molecular docking analysis also revealed strong binding of PIP to key diabetes-related regulatory proteins, including Akt (−6.2 kcal/mol), IR (−7.02 kcal/mol), IRS-1 (−6.86 kcal/mol), GLUT4 (−6.24 kcal/mol), AS160 (−6.28 kcal/mol), and β-arrestin (−6.01 kcal/mol). Hence, PIP may influence the regulation of glucose metabolism through effective interactions with these proteins, thereby controlling blood sugar levels due to its potent antilipidemic and antioxidant properties. In conclusion, our study provides in vivo experimental evidence against the HFD-induced T2DM model for the first time, making PIP a potential natural remedy to enhance the quality of life for diabetic patients and aid in their management. • PIP enhances insulin and glucose tolerance in rats on HFD. • PIP increases IR/Akt/GLUT4 signaling, boosting insulin sensitivity and glucose uptake. • Computational data indicate PIP interacts with IR/Akt/GLUT4 signaling molecules, potentially amplifying their activity. • PIP holds potential as a natural remedy for IR and associated metabolic disorders. [ABSTRACT FROM AUTHOR]