Type 2 diabetes mellitus is increasing worldwide, and the United Arab Emirates is presenting one of the world’s highest prevalence rates. Dietary polyphenols exert an antidiabetic effect by modulating carbohydrates digestion and cellular glucose uptake. Due to their particularly high content in polyphenols, date seeds represent a potential antidiabetic agent. This study aims to determine if date seed polyphenols inhibit the activity of the enzymes (α-amylase and α-glucosidase), responsible for the digestion of carbohydrates and modulating the glucose uptake by human liver cells. In vitro activity of the intestinal α-glucosidase, pancreatic α-amylase, the glucose uptake by HepG2 cells, and the expression of GLUT4 and AMPK analyzed by western blotting (with and without date seeds extract). Our result showed that the maximum enzymes inhibition was obtained with 400 μg/mL and 900 μg/mL DSE for α-amylase and α-glucosidase, respectively. The HepG2 cell viability significantly decreased up to 80% at 4000 μg/mL DSE. The expression of GLUT4 was higher at 100 μg/mL DSE (with insulin and without insulin). However, the expressions of P-AMPK and AMPK were increased by DSE, mainly in a non-insulin-dependent manner. Therefore, DSE, by inhibiting carbohydrate digestion and stimulating glucose uptake by HepG2, can potentially demonstrate the therapeutic potential for diabetes management.