High-pressure homogenization (HPH) has been recently reported to be an effective mechanical cell disruption technology to unlock the intracellular compounds, tightly entrapped in vegetable tissues, using only water as an extraction medium. In this work, HPH was used to promote the recovery of the bioactive compounds contained in white and black sesame seeds (Sesamum indicum). Aqueous suspensions (10% w/w) of the seeds, obtained by high-shear mixing (HSM) for 5 min at 20000 rpm, were treated by HPH at 100 MPa or 140 MPa for up to 10 passes and different temperatures (25 and 50 °C). The HPH treatment caused a considerable cell deagglomeration and fragmentation effect, as shown by the decrease in the size distribution of the suspended particles. At the same time, the HPH treatment also significantly increased, more than two-fold, the polyphenolic content and antioxidant activity of the aqueous extracts, in comparison to HSH. Remarkably, a significant decrease (-20%) in antioxidant activity was observed during HPH processing at a higher temperature, likely due to the degradation of thermolabile compounds. Higher operating pressures increased the antioxidant activity of the aqueous extracts but caused also the increased release of polyphenol oxidases, which induced a higher degradation of the antioxidant activity of the extracts over time in comparison with samples processed at lower pressure. However, spray drying of the HPH-treated suspensions, without any further treatment or additive, resulted in the efficient stabilization of the extracts.