In this study, extraction yield of valuable compounds from brewer's spent grain (BSG) using pressurized liquid extraction (PLE) was investigated varying temperature, solvent type, and flow rate at a constant pressure. The results were compared with Soxhlet extractions using the total phenolic compounds (TPC), total flavonoid compounds (TFC), antioxidant activity (AA), reducing sugars (RS), and total reducing sugars (TRS) as indices. The highest PLE extraction yield was 20.1 wt%, at 120°C, 2 mL/min using ethanol to water volume ratio of 0.5, at 10 MPa. The TPC, TFC, and AA content were favored by water and water/ethanol extractions and temperature increase. The highest AA was obtained with water at 120 °C and 4 mL/min achieving 9944, 4769 and 4096 µmol TE/100 g of BSG extract, respectively. PLE was capable of present high extraction yields maintaining the RS and TRS in the BSG matrix. In addition, BSG was defatted with compressed propane before the extraction with PLE, showing that 2 compressed propane is highly efficient in recovering the lipid fraction from BSG. The results demonstrated a great potential of water and different EtOH/Water solvent ratio at pressurized conditions for obtaining bio-compounds of BSG in a crude extract with expressive biological activity.