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Oral squamous cell carcinoma (OSCC) is an aggressive malignancy that influences patient prognosis and quality of life. Identifying appropriate prognostic indicators may help improve clinical decision-making. This study aimed to evaluate the association of preoperative serum hepatocyte growth factor (HGF) and inflammatory prognostic score (IBPS) with postoperative pathological outcomes in patients with OSCC. A total of 158 subjects were enrolled in this retrospective study (2020-2022), including 79 cases in the A group (healthy control group) and 79 cases in the B group (OSCC group). Serum HGF and inflammatory markers were measured, and IBPS was calculated. Comparative analyses were performed between the A and B groups, and prognostic analyses were conducted within the B-group cohort. Logistic regression was used to examine associated factors, while survival and receiver operating characteristic (ROC) analyses were performed to assess prognostic performance. Baseline characteristics were comparable between the two groups (P > 0.05). HGF levels and IBPS were significantly higher in the B group than in the A group (P < 0.05). In the B group cohort, elevated HGF and IBPS were associated with poorer prognosis (HGF OR = 2.010, 95% CI: 1.046-3.863; IBPS OR = 2.603, 95% CI: 1.316-5.148, P < 0.05) and adverse postoperative pathological outcomes. The combination of HGF and IBPS showed improved discriminative capacity for prognostic prediction (AUC = 0.776, P < 0.001). Preoperative HGF and IBPS are abnormal in OSCC patients and are associated with postoperative pathological outcomes after 20-month follow-up. These observations may support further investigations into preoperative risk stratification and clinical monitoring for patients with OSCC.