Introduction: The oral cavity is affected by a wide range of pathologic lesions that may originate from squamous mucosa, salivary glands, mesenchymal structures and lymphoid tissue. Alterations in Cytokeratin (CK) patterns have been reported in oral potentially malignant and malignant lesions, and its expression is a hallmark of tumour progression. Aim: To evaluate different oral cavity lesions, with an emphasis on using Cytokeratin 8/18 (CK8/18) to differentiate between benign, premalignant and malignant lesions. Materials and Methods: The present hospital-based crosssectional observational study was conducted in the Departments of Pathology and Otorhinolaryngology, Fakhruddin Ali Ahmed Medical College and Hospital, Barpeta, Guwahati, Assam, India, from September 2020 to August 2021. A total of 93 biopsied or resected specimens clinically presenting in the Otorhinolaryngology Department with oral cavity lesions were submitted to the Department of Pathology, Fakhruddin Ali Ahmed Medical College and Hospital for histopathological examination followed by Immunohistochemistry (IHC) with CK8/18 in all the tissue samples as per IHC protocol. Age, gender, clinical presentation and sites of lesions were also assessed, as well as, histopathological evaluation and IHC. All data were collected, compiled and subjected to suitable statistical analysis, such as one-way Analysis of Variance (ANOVA) and Fisher’s exact tests using International Business Machines (IBM) Statistical Package for Social Sciences (SPSS) software version 28.0. Microsoft Office Word and Excel 2019 were used to generate graphs and tables. Results: The age of the patients ranged from 9-90 years and mean±Standard Deviation (SD) age was 52.69±15.81 years. Males, 59 (63.4%), were more commonly affected than females 34 (36.6%), with a male-to-female ratio of 1.73:1. Among the 93 various oral cavity lesions, 24 were located on the buccal mucosa, making it the most common site in our study. Of the 42 malignant oral cavity lesions, the most frequent was moderately differentiated Squamous Cell Carcinoma (SCC) with a frequency of 21 cases (50%), followed by well-differentiated SCC with 18 cases, including one case of Verrucous carcinoma. Poorly differentiated SCC was the least frequent, with three cases (7.14%). CK8/18 was positive in 33 of the 42 malignant cases, four out of the 20 dysplasia cases, and all the benign cases were negative for IHC of CK8/18. The maximal intensity of CK8/18 was seen in 13/21 (62%) cases of moderately differentiated oral SCC. Conclusion: In conclusion, the present study on oral cavity lesions in the lower Assam region highlighted the significance of clinical, histopathological and immunohistochemical evaluations, particularly with CK8/18 staining. A predominance of lesions on the buccal mucosa was found, with moderately differentiated SCC being the most common malignant type. CK8/18 expression showed a notable association with malignant lesions, especially in moderately differentiated SCC, suggesting its potential as a diagnostic marker. These findings contribute to a better understanding of oral cavity pathologies and may aid in early detection and management strategies.