© 2022 The Authors. Published by American Chemical Society.The scope of the study was to optimize high-pressure-assisted extraction (HPAE) conditions for the extraction of phenolic compounds from olive leaves and to compare the optimum HPAE conditions with conventional extraction (CE) (at 50 °C for 30 min). In this regard, different treatment pressure levels (300-500 MPa), time (5-15 min), and solid-to-solvent ratios (0.1-0.3 w/v) were used to optimize the total phenolic content (TPC) and oleuropein content by using the Box-Behnken design. According to the results, optimal HPAE conditions were selected as 433.3 MPa for 15 min with 0.1 w/v solid-solvent ratio to obtain the maximum TPC (57.5 mg GAE/g DW) and oleuropein content (18.45 mg/g DW). Compared to CE, HPAE increased the TPC, antioxidant capacity, and oleuropein content significantly (p ≤ 0.05). Fourier transform infrared spectroscopy results showed no difference between HPAE and CE samples. Based on scanning electron microscopy results, HPAE caused structural changes compared to CE, and this caused to increase the mass transfer rate of phenolic substances.