Natural deep eutectic solvents (NADEs) have emerged as green and sustainable options for the efficient extraction of bioactive components from natural plants. This study aimed to evaluate the effectiveness of NADE-based microwave and ultrasound extraction techniques for sinomenine from Sinomenium acutum, screening nine different NADEs in the process. To optimize the extraction processes, a single-factor experiment was conducted alongside response surface methodology, utilizing a Box-Behnken design. An optimized high-performance liquid chromatography (HPLC) method was also developed to quantify the sinomenine content in various samples. The results revealed that chloride-lactic acid (ChCl-LA) was the most effective NADE for sinomenine extraction, with microwave extraction demonstrating superior efficiency compared to ultrasound extraction. For ultrasound extraction, the optimal parameters included a ChCl-LA ratio of 1:2, 30% of water content, a liquid-to-solid ratio of 1:20, an extraction time of 20 min, and an ultrasonic power of 240 W. In contrast, for microwave extraction, the optimal conditions were a ChCl-LA ratio of 2:1 with 57% of water content, an extraction time of 20 min, and a power level of 423.33 W. Under these conditions, the sinomenine content was found to be 16.03 mg/g for ultrasound extraction and 20.08 mg/g for microwave extraction, respectively. These findings provide a foundation for the further utilization of sinomenine from S. acutum .