Abstract: The multi-component ultrasonic extraction process of Acanthopanax senticosus was optimized via ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) quantitative method and the multi-index comprehensive evaluation method. An UPLC-MS/MS method for the simultaneous quantitative determination of multiple components (chlorogenic acid, syringin, eleutheroside E, isofraxidin, caffeic acid and sesamin) in rhizome of Acanthopanax senticosus was developed. Then, the analytic hierarchy process (AHP) and entropy weight method (EWM) were combined to establish a multi-index comprehensive evaluation method (AHP-EWM method）. Finally, the multi-component ultrasonic extraction process of Acanthopanax senticosus was optimized by single factor combined with response surface methodology (RSM) based on Box-Behnken design (BBD). The results revealed that the optimal process of ultrasonic extraction of multiple components of Acanthopanax senticosus obtained by RSM optimization was as follows: Ultrasonic power 780 W, ultrasonic time 17.5 min, ethanol volume fraction 57%, solid-liquid ratio 1:40 g:mL, raw material particle size 80 mesh. Therefore, the contents of chlorogenic acid, syringin, eleutheroside E, isofraxidin, caffeic acid and sesamin in rhizome of Acanthopanax senticosus were 2235.841±12.17, 517.959±6.09, 861.247±5.30, 66.657±1.22, 45.745±0.77, 99.355±0.69 μg/g, respectively. The comprehensive score based on the AHP-EWM method was 95.45±0.39, which was close to the predicted theoretical value. The effective development of quantitative analysis method and efficient extraction technology of Acanthopanax senticosus have laid a foundation for its resource utilization and pharmacodynamic basic research.