Background: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and oral lichen planus (OLP) is considered a premalignant disease. Objectives: This study aims at comparing the salivary levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), and cancer antigen 125 (CA125) among cases with OSCC, OLP, and healthy persons. Methods: In this case-control study, salivary markers were evaluated in 55 cases (15 patients with OSCC, 20 patients with OLP, and 20 healthy persons); non-stimulated saliva samples were collected from the patients and saliva markers were measured by the enzyme-linked immunosorbent assay (ELISA) method. The data were analyzed, using SPSS 21 software and ANOVA test and P < 0.05 was regarded as significant. Results: Salivary LDH and CA125 levels were significantly higher in OSCC and OLP patients compared to the control group (P < 0.05). Salivary CRP levels were significantly higher in OSCC patients compared to OLP patients (P < 0.05). Besides, salivary CRP levels were higher in OLP subjects than in the control group, but the difference was not significant (P = 0.56). Conclusions: The identification of the salivary LDH, CA125, and CRP may provide a suitable non-invasive predictive tool for malignant changes. However, its use in clinical practice needs further research.