High-pressure ultrasound-assisted extraction technology was applied to extract ferulic acid, senkyunolide I, senkyunolide H, senkyunolide A, ligustilide and levistolide A from Ligusticum chuanxiong rhizomes. Seven independent variables, including solvent type, pressure, particle size, liquid-to-solid ratio, extraction temperature, ultrasound power, and extraction time were examined. Response Surface Methodology (RSM) using a Central Composite Design (CCD) was employed to optimize the experimental conditions (extraction temperature, ultrasonic power, and extraction time) on the basis of the results of single factor tests for the extraction of these six major components in L. chuanxiong rhizomes. The experimental data were fitted to a second-order polynomial equation using multiple regression analysis and were also examined using appropriate statistical methods. The best extraction conditions were as follows: extraction solvent: 40% ethanol; pressure: 10 MPa; particle size: 80 mesh; liquid-to-solid ratio: 100:1; extraction temperature: 70 °C; ultrasonic power, 180 W; and extraction time, 74 min.