Objective: This study aimed to design and optimize the water extraction process for Chuantieling (喘贴灵, CTL) based on the concept of quality by design (QbD). Methods: The single-factor experiments were used to select the best experimental points of CTL water extraction. On this basis, the transfer rate of ephedrine hydrochloride and sinapine thiocyanate, and the yield of the extract were evaluated as the evaluation indicators. The liquid-solid ratio, extraction time, and pH value were selected as the main factors to carry out the Box-Behnken design (BBD). A mathematical model of the critical process parameters (CPPs) and critical quality attributes (CQAs) was established, the interaction between CQAs and CPPs was examined, and the CTL extraction process design space was established and optimized, which guaranteed the stability of the process. The high performance liquid chromatography (HPLC) was used to analyze the main active compounds in the CTL extract. Results: Through single-factor experiments, the best experimental parameters were found to be a liquid-solid ratio of 8∶1, extraction time of 90 min, pH value of 4, and extraction times of three. The experimental variance analysis results of the BBD showed that the P value of the regression model was less than 0.05, and the lack-of-fit value was greater than 0.01, indicating that the constructed model had good predictive ability. The operating space of the CPPs of the CTL water extraction process was combined with the actual production situation. In the production situation, the best extraction process was nine times of water addition, 72 min of extraction time, and 4.5 of pH value. The HPLC results showed that the peak areas of ephedrine hydrochloride, sinapine thiocyanate, tetrahydropalmatine, methyl eugenol, cinnamaldehyde, and 6-gingerol in the CTL extract accounted for 0.94%, 14.32%, 0.78%, 31.23%, 0.34%, and 0.44% of the total peak area, respectively. Conclusion: The water extraction process design space of CTL based on QbD was conducive to actual production operations, ensuring the stability of the process.