Tripterygium wilfordii (TW), which has severe hepatotoxicity, is commonly used as anti-rheumatism. Using the juice of auxiliary herbs in concocting poisonous herbs is a conventional method for toxicity reduction or efficacy enhancement. Traditional Chinese Pharmacy textbooks record that Spatholobi Caulis (SC) can alleviate the side effects caused by TW and also possesses excellent hepatoprotective effect. However, it is still unclear how the concoctive principles of hepatotoxicity reduction and anti-inflammatory efficacy retention of TW after being concocted with the medicinal excipient SC juice. Therefore, this study aimed to evaluate the hepatotoxicity and anti-inflammatory efficacy of concoction with SC juice on TW and preliminarily explored its detoxification mechanism. The attenuation effect of TW concocted with SC juice was determined by triptolide (TP) content, hepatic histological and serum biochemical indexes. The detoxification mechanism was predicted by network pharmacology and molecular docking, and confirmed by quantitative real-time PCR (qRT-PCR) and Western blot. Moreover, the anti-inflammatory efficacy was evaluated by paw edema test, and the major active ingredients in the SC juice introduced to TW concoction were detected. Concoction with SC juice significantly reduced TP content and serum biochemical indicator levels, alleviated liver pathological damage, introduced the main active ingredients, and inhibited the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA). Furthermore, the anti-inflammatory efficacy was retained. In summary, this study elucidated that concoction with SC juice alleviated the hepatotoxicity of TW by inhibiting HIF-1α/VEGFA signaling, decreasing TP content, and introducing the main active components. Moreover, the anti-inflammatory efficacy was retained.