The current study was done to measure the role of piperlongumine (PL) on hyperglycemia interrelated oxidative stress-mediated inflammation and apoptosis, inflammatory stress, and the diabetic insulin receptor substrate 2 (IRS2), protein kinase B (AKT), and glucose transporter 2 (GLUT-2)/4 signaling pathway in streptozotocin (STZ)-persuaded diabetic animals. Diabetes was initiated in experimental animals via a single dose intraperitoneal inoculation of STZ. Diabetic rats revealed an augmented blood-glucose level with drastically diminished plasma-insulin status. The functions of antioxidants were diminished with enhanced lipid peroxidation, conjugated dienes, and protein carbonyls noticed in diabetic rats'  plasma and pancreatic tissues. An elevation of nuclear factor-κB (NF-κB), tumor necrosis factor-α, and interleukin-6 proteins was noticed in pancreatic tissues as well as IRS2, AKT, GLUT-2, and GLUT-4 marker expressions were quantified in the hepatic tissue of control and diabetic rats. Oral administration of PL for 30 days drastically lowered glucose and higher insulin status in STZ-induced diabetic rats. Impressively, PL oral supplementation considerably restored the antioxidant levels and reduced inflammation and diabetic marker expressions in STZ-diabetic rats. These results were supported through a histological study. Moreover, PL also augmented the level of B-cell lymphoma 2 and diminished the level of Bcl-2-associated X protein in STZ-treated rat's hepatic tissues. Thus, we concluded that PL excellently rescued pancreatic β cells through mitigating hyperglycemia via dynamic insulin secretion, activating antioxidants, and inhibiting inflammation and apoptosis in the pancreatic and hepatic tissue of diabetic rats. © 2021 Wiley Periodicals LLC.