SCC is considered to be the most common type of head and neck cancer and its percentage continues to increase. Chemotherapy is considered to be the main line of treatment that is used to treat HNSCC but some patients suffer from many side effects. That’s why researchers continue their investigations to discover the chemotherapeutic drugs with the least side effects. One of the recent chemotherapeutic drugs is Cmab drug that has been approved by the United States of America.Having high affinity towards EGFR, Cmab drug directly acts against EGFR, which is usually overexpressed in invasion and metastasis of malignant tumors. OM is one of the serious side effects of Cmab drug, which may finally lead to altering the whole line of treatment by changing the drug or the dose of the drug. Inflammation of oral mucosa, especially the tongue mucosa, changes the daily functions of the patients as eating, speaking or even swallowing. GSE is one of the potent nutraceutical agents that had been studied for its anti-oxidant and anti-inflammatory effects, in addition to its antimicrobialeffects and cardiovascular benefits. Its beneficial effects are attributed to the unique mix of polyphenolic compounds. Flavonoids, which are the largest groups of polyphenols, are the main components considered to be responsible for the biological properties of GSE. AntiCOX-2 is considered to be an inflammatory immunomarker that is usually not expressed in normal mucosa, but only expressed in the epithelium and connective tissue in cases of inflammation, dysplasia and cancer. GSE has anti-inflammatory and chemopreventive effects by inhibiting COX pathway and decreasing the COX-2 immunoexpression in the inflammed tissues. Examination of H&E stained sections revealed that the use of GSE in groups C&D (taking GSE with Cmab) decreased the atrophy and loss of filiform papillaeof the tongue, in addition to inclination of the muscle atrophy caused by Cmab drug in comparison to group B (taking Cmab drug only). Moreover, an obvious decrease in the inflammation was noticed in groups C&D compared to group B which showed a statistical significance.Examination of COX-2 immunostained sections showed a significant decrease in area percent of COX-2 immunoexpression in the epithelium in groups C&D (taking GSE with Cmab) compared to group B (taking Cmab only). Moreover, taking GSE a week ahead of Cmab yielded better results than when both drugs were given in parallel. By studying the electron micrographs of the four groups, we noticed the strong anti-inflammatory and antimicrobial effects of GSE in reducing atrophy and destruction of tongue papillae with reduction in the number of colonies of microorganisms in groups C&D (taking GSE with Cmab) compared to group B (taking Cmab only). In conclusion, GSE is a potent anti-inflammatory nutraceutical, that when used with chemotherapy could be beneficial in decreasing inflammation and yielding a better tissue response.