Objective To investigate the diagnostic value of changes in serum levels of Urothelial Carcinoma Antigen 1 (UCA1), Tumor Supply Group of Factors (TSGF), and Urokinase-type Plasminogen Activator Receptor (uPAR) in patients with oral cancer (OC) at different TNM stages, as well as their prognostic significance. Methods A total of 60 OC patients admitted to the First Affiliated Hospital of Anhui Medical University and the Second Affiliated Hospital of Anhui Medical University from January to December 2022 were enrolled as the OC group. Additionally, 60 patients with oral diseases admitted during the same period were enrolled as the control group. Serum levels of UCA1, TSGF, and uPAR were collected from all patients upon admission, and their correlations with OC and different TNM stages of OC were analyzed. Results The levels of UCA1, TSGF, and uPAR were higher in the OC group compared to the control group, and were also higher in patients with stage Ⅲ-Ⅳ OC compared to those with stage Ⅰ-Ⅱ OC (P<0.05). A follow-up of 8 months was conducted on the 60 OC patients, with no loss to follow-up until February 2024. By the end of the follow-up, 56 patients were still alive, while 4 patients had died due to recurrence of the primary tumor. Patients with high expression of UCA1, TSGF, and uPAR had significantly shorter survival times compared to those with low expression (HR=0.01, 0.01, 90.28, respectively; P<0.05). Pearson correlation analysis showed a positive correlation between serum levels of UCA1, TSGF, and uPAR with OC, as well as with stage Ⅰ-Ⅱ and stage Ⅲ-Ⅳ OC (P<0.05). The areas under the curve (AUCs) for the combined diagnosis of OC, stage Ⅰ-Ⅱ OC, and stage Ⅲ-Ⅳ OC using serum UCA1, TSGF, and uPAR were 0.823, 0.777, and 0.777, respectively (P<0.05). Conclusion High expression of serum UCA1, TSGF, and uPAR levels in OC patients is associated with their prognosis. Detection of serum levels of these biomarkers may be beneficial for diagnosing OC and differentiating between different TNM stages.