Background: Effects on insulin sensitivity and postprandial glycemia through enzyme inhibition and regulation of glucose transport have been extensively researched; however, the role of sugarcane (poly)phenols remain underexplored. Methods: In a randomized, placebo-controlled, single-blinded crossover study, 12 healthy participants consumed a bread-based meal containing 50 g of carbohydrates, supplemented with either 0.5% or 5% liquid PRSE or sugar-balanced controls. Glucose and plasma insulin levels were assessed over 180 min. The extract was evaluated for its inhibitory effect on human α-amylases (salivary and pancreatic) and α-glucosidases (sucrase, maltase, and isomaltase) utilizing solid PRSE. Results: The postprandial glucose and insulin responses to bread sandwiches in healthy volunteers remained unchanged by both PRSE dosages. High-dose treatment reduced the Matsuda index by 9.8%, perhaps due to a subtle alteration in whole-body insulin sensitivity. Low-dose intervention postponed the insulin peak by 30 min without altering HOMA-IR. In vitro, PRSE diminished sucrase activity by 67% (IC₅₀ = 425.8 ± 18.7 µg/mL) and lowered maltase and isomaltase activity by 40% (IC₂₅ = 876.3 ± 131 and 960.6 ± 95.2 µg/mL, respectively). It enhanced the activity of human salivary and pancreatic α-amylases. Conclusion: In healthy people, acute PRSE supplementation had a minor impact on postprandial glucose and insulin levels. Low-dose PRSE postponed the insulin peak, whereas high-dose PRSE reduced Matsuda index potentially via α-amylase activation, suggesting a modest alteration in whole-body insulin sensitivity without significantly changing the glucose or insulin response. In vitro, PRSE exhibited modest inhibition of human α-glucosidases.