Objective: This study conducted a systematic review of drug interactions among Korean insurance herbal medicines and performed experimental validation of hepatoprotective interactions with acetaminophen, along with genotoxicity assessments to establish evidence-based safety guidelines for clinical practice. Methods: A systematic literature review was performed using PubMed, Google Scholar, and Web of Science databases, identifying 27 eligible studies from 2,011 initial records. For experimental validation, hepatoprotective effects of Korean medicine (BJIKT) were evaluated in HepG2 cells. Cell viability, combination index (CI), cytochrome P450 enzyme expression, reactive oxygen species (ROS) levels, and glutathione (GSH) content were assessed. In vivo studies examined CYP enzyme expression in mouse liver tissue following acetaminophen administration with BJIKT treatment. Genotoxicity evaluation was also conducted. Results: The systematic review revealed that BST was among the most extensively studied formulations (6 studies), demonstrating safe combination profiles with anticoagulants and beneficial effects in reducing chemotherapy-induced oral mucositis. Experimental validation of BJIKT showed significant hepatoprotective effects against acetaminophen-induced toxicity. In HepG2 cells, BJIKT combined with acetaminophen demonstrated strong protective effects (CI = 0.38), while lower concentrations showed no interaction (CI = 1.00). BJIKT significantly reduced acetaminophen-induced CYP2E1 expression, decreased ROS production, and restored GSH levels. In vivo studies confirmed that BJIKT modulated hepatic CYP enzyme expression, particularly reducing acetaminophen-induced CYP2E1 and CYP1A2 upregulation while maintaining CYP2D6 and CYP3A4 at physiological levels. Genotoxicity assessments revealed no mutagenic potential for either BJIKT or BST across all test systems. Conclusions: These findings establish evidence-based foundations for safer integration of traditional Korean medicines with conventional therapies and support the use of specific formulations as adjuvant therapy.