Background: Study was conducted to investigate the etiopathogenesis of squamous cell carcinoma (SCC) in cattle and buffalo through pathoepidemiological, histopathological, immunohistochemical and molecular analysis. 
 
Methods: A total of 64 tissue samples of SCC were collected between December 2024 and December 2025.&nbsp; Immuno histo chemistry (IHC) was performed to detect immunoexpression of pan cyto keratin (PCK), proliferating cell nuclear antigen (PCNA), zonula occludens-1 (ZO-1), E-cadherin, Vimentin, FOXA1, p120, GATA3, &gamma;-H2AX and p63. Polymerase chain reaction (PCR) was performed to detect papillomavirus. 
 
Result: Out of 64 cases, ocular tumors were the most prevalent, followed by horn cancer (34.38%) and vulvar tumors (9.37%). Cattle accounted for 87.5% cases, with crossbred Holstein-Friesian showing the highest occurrence. SCC was most frequently observed in females and in animals aged 7-10 years. Histopathologically, most tumors were well differentiated (WD) (70.31%). Immunohistochemically, SCCs exhibited strong expression of PCK, PCNA, p120, &gamma;-H2AX and p63, while ZO-1 showed moderate expression. Upregulation of vimentin and downregulation of E-cadherin indicated epithelial-mesenchymal transition (EMT), whereas increased &gamma;-H2AX expression suggested enhanced DNA double-strand damage in poorly differentiated tumors. PCR confirmed the presence of papillomavirus in four (6.25%) SCC cases.

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Patho-epidemiological and Immunohistochemical Study of Squamous Cell Carcinoma in Cattle and Buffaloes