<h3>Background</h3> Proteomics, which focuses on evaluating a range of proteins, has emerged as one of the main analytical strategies in cancer research. A number of proteins may show alteration in oral cancer and high-risk potentially malignant disorders such as oral submucous fibrosis. Salivary diagnostics has received increasing importance owing to its ease of collection, proximity to the lesion, and efficient analysis of different proteins and peptides present in saliva. <h3>Objective</h3> (1) To evaluate the salivary proteomic profile in healthy controls, oral submucous fibrosis, and oral squamous cell carcinoma. (2) To compare the differential regulation of proteins among the 3 groups. <h3>Methods</h3> Saliva samples were collected from the study participants using standard protocols. The samples were processed and proteomic analysis was performed using Orbitrap high-performance liquid chromatography-mass spectrometry. Data analysis of the altered proteins was done using Thermo Proteome Discoverer 2.2. UniProt Homo sapiens was the database used for the identification and comparison of proteins. Further, differentially regulated proteins in oral submucous fibrosis and oral squamous cell carcinoma were evaluated. <h3>Results</h3> The proteins that were upregulated in the diseased group included alpha 1 antitrypsin, S-100 protein, histone, and adenylyl cyclase–associated proteins. Downregulated proteins included glucose-6-phosphate 1-dehydrogenase, statherin, calponin, lactoferrin, small proline-rich protein, and interleukin-1 receptor antagonist protein. <h3>Conclusions</h3> Differentially regulated proteins may serve as potential biomarkers in early diagnosis of oral cancer and in understanding the behavior of oral potentially malignant disorders.