Background: The utilization of molecular techniques in detecting cancer has resulted in an improved prediction of outcomes. Oral squamous cell carcinoma (OSCC) is a prevalent illness that is frequently detected in its late stages. Therefore, finding molecular biomarkers that lead to the early detection of OSCC is of great importance. Objectives: This study aimed at evaluating the expression levels of long non-coding RNA (LncRNA) gastric carcinoma highly expressed transcript 1 (GHET1) and lncRNA ZXF2 in OSCC patients and their relationship with clinical pathology variables due to biomarker discovery and early diagnosis of OSCC. Methods: Tissue sampling was performed after selecting 30 OSCC patients and 30 healthy individuals from Emam-Khomeini Hospital, Tehran, Iran. Then, RNA extraction and cDNA synthesis were performed from these samples, using the relevant kits and their quantity and quality were measured, using nanodrop and agarose gel electrophoresis, respectively. For molecular biomarker identification and validation, real-time PCR (RT-PCR) was utilized to assess the expression of lncRNA GHET1 and lncRNA ZXF2. Data analysis was done, using GraphPad prism V.8 software. Results: The results showed that the expressions of both lncRNA GHET1 and lncRNA ZXF2 in OSCC tumor tissue increased compared to normal tissue (P < 0.0001). Receiver operating characteristic (ROC) analysis indicated that lncRNA GHET1 and lncRNA ZXF2 have the capability to be employed as biomarkers for OSCC detection. However, no significant relationship was observed between lncRNA GHET1 and lncRNA ZXF2 expressions with clinicopathological variables such as tumor stage and grade as well as patients' age. Conclusions: LncRNA GHET1 and lncRNA ZXF2 have the potential to be used as biomarkers in the early detection of OSCC and evaluating their expression in clinical settings are recommended. The use of these biomarkers in the early detection of OSCC can prevent the high mortality rate of OSCC patients. In the current study, the important role of the studied lncRNAs in OSCC diagnosis was shown. However, further studies are needed to confirm this.