Objective: To investigate the expression and clinical significance of telomere repeat binding factor 2 (TRF2) in gastric cancer. Methods: UALCAN was used to analyze the expression of TRF2 in gastric cancer patients. Clinical patient samples were used to verify their protein expression levels by immunohistochemistry. Kaplan-Meier methods were used to analyze the relationship between overall survival rate and clinical features of GC patients. TIMER was used to analyze immune infiltration in gastric cancer patients. Various online analysis tools were used to explore the potential relationship between TRF2 and gastric cancer, and CTD and SymMap databases were used to screen candidates for drugs targeting TRF2 gene. Results: The expression level of TRF2 in GC patients was higher than that in normal subjects (P < 0.05). Patients with high TRF2 expression in gastric cancer had a poorer prognosis (P < 0.05). TRF2 expression was correlated with methylation, gene mutations, immune cell abundance, and expression of immune markers in gastric cancer (P < 0.05). The expression level of TRF2 was positively correlated with the patient’s age, gender, race, tumor stage, tissue typing, and body weight (P < 0.05). TRF2-related gene enrichment analysis showed that these genes were mainly concentrated in focal adhesion, calcium signaling pathway, purine metabolism, thyroid hormone signaling pathway, FoxO signaling pathway, and so on. Small molecule drugs such as aristolochic acid I, arsenic, and β-methylcholine, and traditional Chinese medicines such as Szechwan Chiberry Fruit and root of Common Monkshood may have potential value in the treatment of gastric cancer. Conclusion: TRF2 is highly expressed in gastric cancer and is associated with poor prognosis, and participates in the regulation of a variety of biological functions of gastric cancer. Small molecule drugs represented by aristolochic acid I and arsenic, and traditional Chinese medicine represented by Szechwan Chiberry Fruit and root of Common Monkshood may be potential targeted drugs for the treatment of gastric cancer.