Curcumin can inhibit the proliferation and metastasis of a variety of tumor cells, including oral tumor, but its use is severely limited by its low bioavailability and stability. In this study, transferrin-modified liposomal curcumin was constructed to detect its inhibition on oral squamous cell carcinoma cell line HN4 and compared with liposomal curcumin and curcumin solution (curcumin dissolved in PBS (pH7.4, 0.01Mol/L)). Firstly, curcumin solution (Cur), liposomal curcumin (Cur-Lips) and transferrin-modified liposomal curcumin (Tf-Cur-Lips) were prepared. The regulatory effects of Cur, Cur-Lips and Tf-Cur-Lips on the internal and external disposal of curcumin were investigated by curcumin release in vitro and pharmacokinetics in vivo in rats. Then, HN4 cells were treated with Cur, Cur-Lips and Tf-Cur-Lips at different concentrations, respectively, and cck-8 was used to detect the effect of different experimental groups on HN4 cells proliferation. Finally, to investigate the molecular mechanism of curcumin inhibiting the proliferation and apoptosis of HN4 cells, the expression levels of apoptosis-related genes P53 and Fas was detected and compared by real-time fluorescence quantitative PCR in Cur, Cur-Lips and Tf-Cur-Lips groups. We found that compared with Cur, Cur-Lips metabolic time was significantly prolonged, and transferrin modification could further improve the stability of liposomal curcumin and prolongate liposomal curcumin metabolic time. Compared with Cur and Cur-Lips, Tf-Cur-Lips can significantly enhance the proliferation inhibition of HN4 cells, induce their apoptosis, and up-regulate the expression of apoptosis-related genes P53 and Fas. In conclusion, compared with Cur and Cur-Lips, Tf-Cur-Lips have stronger inhibitory effect on oral squamous cell carcinoma cell line HN4. This study will provide a new option for construction a long-term targeted curcumin delivery system against oral squamous cell carcinoma.