High grade gliomas (HGGs), are the most malignant and difficult to treat brain tumors. Despite several studies on glioma pathobiology there is no comparative proteomics study on high-grade and low-grade gliomas which uncovers the mechanism behind the aggressive mesenchymal behaviour of HGGs. In this study, tissue samples of high-grade and low-grade gliomas were processed for label free quantification (LFQ) using HR-LC MS/MS. The analysis identified 140 differentially expressed proteins, GSEA and protein-protein interaction analysis showed over expression of pathways like; ECM remodelling, Focal Adhesion, EMT and Glycan Biosynthesis in HGG. The key proteins were validated using multiple reaction monitoring experiment. ECM glycoproteins including; Fibronectin, Fibrinogens, Collagens, Vitronectin along with mesenchymal markers such as Vimentin and TGF-β came over-expressed in HGGs. The over-expression of oligosaccharyltransferase in HGG indicates its role in enhanced expression of glycoproteins. In-silico molecular docking with catalytic subunits of OST identified two small molecule inhibitors; Irinotecan and Entrectinib as potential candidates to target OST. We propose OST plays a major role in tumor metastasis by promoting EMT and could be used as a potential target to suppress glioma metastasis. Finally, the proteins identified in this study need further clinical research to validate their prognostic values as protein markers.