Smoking is one of the main risk factors in the development of various oral health disorders, including oral cancer and periodontal disease. Tobacco smoke exposure not only physically affects the oral mucosa but also triggers significant molecular and genetic changes. Transcriptome, defined as the complete set of RNA transcribed in a cell, serves as an important indicator in understanding the biological impact of tobacco smoke carcinogens on oral epithelial cells. This study aims to identify the content and pathogenesis of tobacco smoke on human oral mucosa, understand the theoretical concept of the oral mucosal transcriptome, and analyze the relationship between the pathophysiology of tobacco smoke exposure and transcriptomic changes in human oral mucosa. This study was conducted using a literature review method, based on previous research found through Google Scholar that discusses the effects of tobacco exposure on the oral mucosal transcriptome. Tobacco smoke exposure has been proven to cause significant dysregulation in gene expression within oral epithelial cells. The disrupted molecular pathways include Wnt signaling, integrin signaling, and Rac protein activity, which are associated with carcinogenesis. Additionally, mutations in the tumor suppressor gene p53 were found in smokers, indicating early signs of cellular transformation toward oral cancer. Smoking has distinct effects on the transcriptome by stimulating inflammatory and oxidative responses. These results indicate that transcriptome analysis can serve as a molecular approach to understanding the pathogenesis of smoking-related oral cavity disorders and provide a foundation for the development of biomarker-based preventive strategies.