ABSTRACT Background The molecular profile of cells within the tumor invasive zone, where tumor cells interact with surrounding non‐tumor cells, plays a crucial role in defining tumor malignant characteristics, such as the pattern of invasion (POI). Therefore, evaluating the diagnostic value of the proliferation index molecule, Ki‐67, in both tumor cells and adjacent non‐tumor cells at the invasive zone with different POIs, holds significant clinical importance for oral squamous cell carcinoma (OSCC). Methods This retrospective study included 133 primary OSCC samples, and the spatial pattern of Ki‐67 in the tumor invasive zone was analyzed by immunohistochemistry (IHC). The prognostic value of tumor cells and stroma proliferative capacity in different POIs were assessed. Results Ki‐67 was widely expressed in tumor cells and stroma cells within the invasive zone, and cells in high‐invasiveness POIs exhibit higher proliferation. Elevated Ki‐67 expression in tumor cells was associated with poor overall survival (OS) and disease‐free survival (DFS) in patients, which is independent of POIs. In our study, we identified the expression level of Ki‐67 in tumor cells across high‐invasiveness POIs as an independent risk factor for OS and DFS in OSCC patiens. Additionally, Ki‐67 expression in surrounding non‐tumor cells did not significantly correlate with patient survival. Conclusion The remarkable proliferation characteristic of tumor cells in high‐invasiveness POIs of OSCC tumors plays a crucial role in the prognosis of patients.