Background: An investigation was carried out on twelve clinical cases of neoplasm of horn in Durg, Dhamtari and Rajnandgaon districts of Chhattisgarh, suspected of bovine horn core carcinoma (squamous cell carcinoma) revealed the cytology, pathomorphology and immunohistochemical (IHC) expression of Pan-cytokeratin (Pan- CK), p53 gene, epidermal growth factor receptor (EGFR) and p16 gene in tumourous growth at horn in bovines. Methods: In this field-laboratory investigation conducted during January to June 2022, we explicate the cytological, pathological and immunohistochemical alterations in bovine horn core carcinoma from 12 tissue samples. Cytological studies includes special papaniculaou staining and immunohistochemistry was performed through Benchmark automated staining system. Result: Eight out of 12 cases (66.66%) were confirmed as SCC of horn on the basis of histopathological and immunohistochemical analysis. Papanicolaou staining revealed variation in shape and size of cells and altered nuclear details. Grossly unilateral large cauliflower like neoplastic growth at the base of the horn was observed. Differentiation of tumours were based on histopathology and Immunohistochemistry. Well differentiated SCCs (n=4; 50%) were characterized by severe keratinization of horn epithelium with concentric arrangement forming keratin pearls also called as “cell nests”. Moderately differentiated SCCs (n=2; 25%) characterized by small keratin pearl formations and mitotic figures. Poorly differentiated SCCs of horn (n=2; 25%) revealed absence of distinctive keratin pearls although deep invasion from primary site was observed. Tissue samples revealed strong immunohistochemical staining of Pan-CK, p53 and EGFR and negative to p16. Highest immunohistochemical expression was observed in Pan-CK which confirmed the tumours were of epithelial origin and EGFR immunoexpression was confirmatory for malignancy and degree of metastasis.