Objective To explore the effect of the pressure, time, and section thickness of high hydrostatic pressure treatment on the quality and phenylethanoid glycoside extraction amount of desert cistanche.Methods The application parameters of high hydrostatic pressure treatment for cistanch are optimized by single factor experiment combined with response surface optimization.Results The results of single factor optimization show that with the increase of pressure (100~500 MPa) and treatment time (10~25 min), the color difference, hardness, and phenylethanoid glycoside extraction amount of cistanche are increased. With the increase of section thickness (2~10 mm), the color difference of cistanche is increased, but the hardness and phenylethanoid glycoside extraction amount are decreased. The optimal parameters are 200~300 MPa, 15~25 min, and 2~6 mm. Response surface optimization results show that pressure has a more significant effect on the extraction amount of phenylethanoid glycoside. The extraction amount of phenylethanoid glycoside is higher at a pressure of 294.341 MPa, a time of 14.658 min, and a section thickness of 3.644 mm, with a value of （5.35±0.21） mg/g.Conclusion The pressure in high hydrostatic pressure treatment is the primary factor to improve the quality of cistanche and promote the extraction of phenylethanoid glycoside. In contrast, the thinning effect of section thickness and the moderate extension of treatment time are the secondary factors that affect the amount of phenylethanoid glycoside.