In rats, a fructose-rich diet triggers endocrine-metabolic disturbances similar to those present in human prediabetes. We evaluated the protective effect of isoespintanol, a monoterpene isolated from Oxandra cf. xylopioides (Annonaceae), on pancreatic islet. Rats were kept for three weeks with a standard commercial diet and tap water (C), plus 10% fructose (F), or F plus isoespintanol (I; 10 mg/kg, i.p.). Glycemia, triglyceridemia, total cholesterol, HDL-cholesterol, insulin resistance index (IRX), and glucose tolerance tests were determined. Glucose-stimulated insulin secretion (GSIS) and gene expression of insulin signalling mediators (insulin receptor -IR-, IRS1/2, PI3K), oxidative stress (SOD-2, GPx, GSR, 3’-nitrotyrosine), inflammation (TNF-α, IL-1β, PAI-1), mitochondrial function (Bcl-2, mtTFA, PGC-1α), and apoptosis markers were evaluated in pancreatic islets. The F group increased triglyceridemia, non-HDL-cholesterol, and IRX, and decreased HDL-cholesterol and impaired glucose tolerance, with alterations reversed by isoespintanol administration (p < 0.05). Isoespintanol normalized higher GSIS recorded in the F group. F decreased mRNA levels of insulin signalling mediators and mitochondrial function markers, and increased the expression of inflammatory, apoptotic, and oxidative stress markers, alterations that were significantly reversed by isoespintanol. Current results suggest that isoespintanol improved insular oxidative stress and inflammation by affecting the IR-PI3K pathway, which plays a pivotal role in insulin resistance development, underlying its therapeutic potential for the prevention of type 2 diabetes before its onset (prediabetes).