Examining the intricate changes in the extracellular matrix (ECM) dynamics has become a focal point in our ongoing exploration of carcinogenesis. Our study delves into the dynamic modulation of fibronectin (FN), a pivotal ECM protein, during hepatocellular carcinoma (HCC). A comprehensive analysis combining clinical and statistical methodologies identified elevated FN levels in HCC patients, exhibiting a 2.1 and 1.7-fold increase compared to fibrotic and cirrhotic patients, respectively. Moreover, the area under receiver operating characteristic curve (AUC=0.89) of FN displayed its ability to distinguish between HCC and cirrhosis patients with specificity of 80.4% and sensitivity of 83.7%. Furthermore, ROC curves of FN displayed an AUC of 0.93 with specificity of 86% and sensitivity of 83.7%, this was for separating all non-cancerous patients from HCC. Additionally, HCC patients demonstrated distinctive histological features such as vascular invasion, nodules count, and tumor size, underscoring FN's substantial role in HCC progression. Our findings unequivocally highlight the significant involvement of FN in the development of hepatocellular carcinoma.