Cluster of differentiation (CD)47, which acts as a negative indicator for phagocytic cells, is overexpressed on the surface of multiple human solid tumor cell types. Avoiding phagocytosis by CD47 is required for the progression of solid tumors. The present study investigated the expression of CD47 in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and preliminarily explored the impact of CD47 on the proliferation of OSCC cells. A total of 56 tissue samples, including 36 cases of OLK, 10 cases of OSCC and 10 cases of normal oral mucosa (NOM) were selected to detect the expression of CD47 by immunohistochemistry. For subgroup analysis, OLK samples were divided into OLK with low-risk dysplasia (LR-OLK) and OLK with high-risk dysplasia (HR-OLK). The subcellular localization of CD47 was determined by immunofluorescence in three OSCC cell lines (Tca8113, SCC-9 and Cal-27). The effect of CD47 antibody on the proliferation of the Cal-27 cell line was analyzed using the Cell Counting kit-8 assay. CD47 expression in OLK and OSCC lesions was significantly higher than in NOM (P<0.05). Compared with LR-OLK, the expression of CD47 in HR-OLK and OSCC cells was upregulated (P=0.0327 and P=0.0048, respectively). CD47 was highly expressed in OSCC cell lines (Tca8113, Cal-27 and SCC-9) and weakly expressed in normal oral keratinocytes. The proliferation of Cal-27 cells was inhibited by CD47 antibody in a concentration and time-dependent manner. CD47 may be a reliable biomarker for predicting the progression of oral precancer and cancer, and it may serve as an important molecular target for designing a novel therapy for oral cancer.