Sorafenib serves as a first-line treatment for advanced hepatocellular carcinoma (HCC), advanced renal cell carcinoma (RCC), and radioactive iodine-refractory differentiated thyroid carcinoma (DTC). While it improves patient prognosis by inhibiting tumor cell proliferation and angiogenesis, approximately 70% of patients experience limited efficacy within 6 months of treatment due to primary or acquired resistance mechanisms. These mechanisms include abnormal activation of core signaling pathways, epithelial-mesenchymal transition (EMT), dysregulated ferroptosis, aberrant drug transport and metabolism, and abnormal regulation of the tumor microenvironment (TME). Based on resistance mechanism subtypes, this systematic review summarizes recently reported extracts from traditional Chinese medicine (TCM) and natural product monomers that demonstrate the potential to reverse sorafenib resistance. It further provides an in-depth analysis of the current challenges in resistance research. These challenges encompass the mismatch between pharmacokinetic properties and resistance mechanism subtypes (e.g., precipitation of lipophilic components in the acidic TME, metabolic competition), the unclear core targets and cooperative interaction patterns within resistance subtypes (e.g., undefined contribution of multiple mechanisms), and the lack of standardization and continuity in clinical trials and translation (e.g., absence of subtype stratification, disconnection between quality standards and mechanisms). To address these challenges, this review proposes innovative directions, including the development of mechanism-oriented customized drug delivery systems, multi-omics-driven elucidation of core targets and construction of cooperative networks, and the establishment of clinical translation systems stratified by resistance mechanism subtypes. This review aims to provide insights for deepening fundamental research on the combination of TCM/natural products with sorafenib for treating advanced cancer and to promote its standardized clinical application, thereby fostering the development of integrated Chinese-Western medicine strategies in oncology.