Hempseed hull, an underutilized by-product of the hemp processing industry, is a valuable bio-based material. This study aims to optimize phenolic compound extraction by natural deep eutectic solvents (NADES) with enhanced antioxidant properties (DPPH, FRAP, ABTS). By utilizing a chemometric approach, the research was conducted in three stages: selecting high-extractability NADES, identifying crucial extraction variables via screening, and optimizing conditions using response surface methodology (RSM). Fractional factorial experimental design was employed to identify the important variables, while a face-centered central composite experimental design (CCD) was utilized in combination with response surface methodology (RSM) to determine the optimal extraction conditions. The optimal conditions were found using NADES based on L-proline and lactic acid (1:2 ratio) at 39°C for the liquid-solid ratio, 70°C for temperature, and 135 minutes for extraction time. By optimizing extraction conditions this study contributes to advancing our understanding of hempseed hulls' biochemical composition and its potential as bio-based material.