Oral Squamous Cell Carcinoma (OSCC) is a dreadful disease with no clinically proven biomarker till date and the 5-year survival rate has not improved past few years. Better understanding of deregulated genes involved in the advanced stage tumor (stage III and IV) and further comparison with early stage tumor (Stage I and II) might lead to the discovery of biomarkers that can identify the tumor at an early onset. In this study we examined the gene expression profile of advanced OSCC tumors using an Affymetrix Human Gene-1.0ST array and compared with control tissue surrounding normal margins. Data analysis and pathway analysis was performed using xRAY-Biotique and Ingenuity Systems to identify advanced OSCC gene profile with statistically significant differential expression of candidate marker genes and to generate pathways deregulated in advanced OSCC. It was found that hepatic stellate cell activation, G2/M transition, interferon signaling, dendritic cell maturation and oncostatin-M signaling are the top significant pathways in promoting two important processes, fibrosis and inflammation. Validation studies, quantitative-PCR and immunohistochemistry, has led to identification of FN1 expression that can significantly distinguish early and advanced OSCC at mRNA and protein level. Meta-profiling analysis using present and external microarray data that includes dysplasia gene profile revealed that loss of KRT4 in pre-malignant stage might be an indicator for oral cancer progression. It has also revealed that MMP13 and SPP1 expression has not changed in dysplasia condition. But their mRNA levels increases in early and advanced tumor condition. SPP1 and MMP13, promoters for fibrosis and inflammation, are essential for disease progression and siRNA studies showed decreased cell migration and invasion in OSCC cells. A better understanding of molecular interactions in advanced OSCC samples has provided a clear insight of role of significant pathways and genes involved in the development of markers for early detection (FN1), prediction (loss of KRT4 in dysplasia condition) and therapeutic (targeting SPP1 and MMP13) purposes for improving the survival rate of patients.