Based on the concept of quality by design(QbD), this study optimized the processing technology of Ilicis Rotundae Cortex. According to the processing method and ingredient requirements of Ilicis Rotundae Cortex in the Chinese Pharmacopoeia, the content of syringin and pedunculoside, alcohol extract, fragmentation rate, and moisture content were taken as the critical quality attributes(CQAs). The soaking time, moistening time, and drying time were taken as critical process parameters(CPPs) by single factor tests. The weight coefficients of CQAs were determined by the analytic hierarchy process(AHP)-entropy weighting method, and the comprehensive score was calculated. With the comprehensive score as the response value, Box-Behnken design was employed to establish a mathematical model between CPPs and CQAs, and the design space for the processing of Ilicis Rotundae Cortex was built and verified. The results of ANOVA showed that the mathematical model had the P value below 0.05, the lack of fit greater than 0.05, adjusted R~2=0.910 5, and predicted R~2=0.831 0, which indicated that the proposed model had statistical significance and good prediction performance. Considering the factors in production, the best processing conditions of Ilicis Rotundae Cortex were decoction pieces of about 1 cm soaking for 1 h, moistening for 4 h, and drying at 60-70 ℃ in a blast drier for 2 h. The optimized processing technology of Ilicis Rotundae Cortex was stable and feasible, which can provide a reference for the standardized preparation and stable quality of Ilicis Rotundae Cortex.