BACKGROUND: Sorafenib, a multi-kinase inhibitor, is a key therapeutic agent in the treatment of advanced hepatocellular carcinoma (HCC), metastatic renal cell carcinoma (RCC), and radioactive iodine-refractory differentiated thyroid cancer (DTC). However, its clinical efficacy is frequently hampered by the rising prevalence of sorafenib resistance, particularly in HCC. This reality underscores the urgent need for a comprehensive pan-cancer investigation to elucidate the underlying mechanisms of resistance. METHODS: We employed a systematic bibliometric approach utilizing the Web of Science Core Collection to conduct a structured literature search. Performance analysis and visualization were conducted using VOSviewer and CiteSpace. A triphasic screening protocol was implemented to identify publications focused on sorafenib resistance, covering a period from 2006 to 2025. RESULTS: Our analysis identified 1,484 eligible publications, with a peak of 194 articles published in 2022. The majority of research (79.48%) centered on HCC, with significant contributions from institutions in China and the United States. Co-authorship and keyword network analyses revealed a robust interdisciplinary collaboration landscape. Key themes emerged, including dysregulation of drug transporters and clearance mechanisms, metabolic reprogramming, programmed cell death, interactions within the tumor microenvironment, and epigenetic regulatory mechanisms, highlighting critical areas contributing to resistance. CONCLUSION: This study highlights the current research landscape concerning sorafenib resistance, facilitating the identification of emerging trends and research gaps. Future research priorities should include biomarker-driven clinical trials, the development of nanoparticle delivery systems, and the clinical translation of combination therapy strategies. Additionally, the integration of deep learning algorithms in the context of big data has the potential to enhance our understanding of resistance mechanisms , ultimately aiming to overcome resistance challenges and improve patient survival outcomes.