Background Increased levels of lactate dehydrogenase (LDH) as a tumor marker have been reported in malignant and some premalignant oral lesions such as oral lichen planus (OLP) and oral lichenoid reactions (OLRs). This study aimed to assess the level of total LDH in the saliva and serum of patients with oral squamous cell carcinoma (OSCC), OLP and OLRs. Methods In this case–control study, the participants were divided into four groups (n = 25) of healthy controls, OLP, OLRs, and OSCC. The serum and stimulated/unstimulated salivary levels of LDH were spectrophotometrically measured using standard LDH kits (Pars Azmoun). One-way ANOVA, Chi-square test, Pearson’s correlation test, and receiver operating characteristic (ROC) analysis were applied to analyze the data. Results The serum and salivary levels of LDH in OSCC patients were significantly higher than that the corresponding values in other groups (P = 0.0001). The serum level of LDH in OLR group was significantly higher than that in the control and OLP groups (P = 0.0001), but the difference in salivary level of LDH was not significant. The ROC analysis showed that both the serum and salivary levels of LDH had significant diagnostic ability for detection of OSCC and OLRs. Significant associations were noted between the serum and salivary levels of LDH. Conclusions Patients with OSCC and OLRs had higher serum levels of LDH than OLP and control groups. Further prospective longitudinal studies are required to assess the tissue level of LDH and monitor the transformation of OLRs because they have low rate of malignant transformation compared with other oral premalignant lesions.