Background <p>The decoction process of compound formulae is a critical procedure in traditional herbal medicine for reducing toxicity and preserving efficacy. However, due to the high complexity of herb ingredients and chemical constituents in the formulae, precise real-time monitoring of the dynamic changes in the decoction system and accurately predicting its optimal endpoint remain significant challenges that current technologies struggle to address.</p> Purpose <p>To develop an online real-time mass spectrometry (ORT-MS)-driven strategy for real-time monitoring complex components during the decoction of compound formulae, and to establish a validated schema for predicting the optimal decoction endpoint, using Zhenwu Decoction as a case study.</p> Results <p>A novel ORT-MS monitoring device was established successfully, enabling continuous long-term (&gt; 240&#xa0;min) MS monitoring of various compounds in Zhenwu Decoction. By quantitatively tracking the decoction profiles of key toxic (e.g., hypaconitine) and bioactive (e.g., benzoylhypaconitine) compounds, a method for evaluating overall toxicity/bioactivity of the decoction was built. Furthermore, a comprehensive schema for determining the optimal decoction endpoint was proposed, integrating five-dimension: safety, bioactivity, time, energy consumption, and financial cost (SBTEF). The results demonstrated, under the experimental conditions and dosage adopted in this study, that the optimal decoction endpoint for Zhenwu Decoction is about 150&#xa0;min when all factors are considered.</p> Conclusion <p>This study proposes a universal MS-driven real-time analysis strategy and endpoint prediction schema for herbal medicine decoction process, providing a novel scientific tool for decoction quality evaluation (especially toxicity attenuation/efficacy preservation) to promote herbal medicine quality and rational clinical use.</p>